Guidelines on the Prevention and Control of Tuberculosis in Ireland

<strong>Guidelines</strong> on the Prevention and Control ofTuberculosis in Ireland 2010National TB Advisory CommitteeApril 2010Amended 2014ISBN: 978-0-9551236-5-8

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCPublished by Health Protection Surveillance Centre25-27 Middle Gardiner StreetDublin 1Tel: 01-8765300Fax: 01-8561299© Health Protection Surveillance Centre 2010-ii-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCContentsNational TB Advisory CommitteeTerms of referenceForewordKey recommendationsvviiviiiix1. Epidemiology and Surveillance of Tuberculosis...................................................................11.1 Global trends........................................................................................................................... 11.2 Tuberculosis in Europe............................................................................................................. 21.3 Tuberculosis in Ireland............................................................................................................. 31.4 Surveillance of TB.................................................................................................................... 51.5 Notification Procedures........................................................................................................... 71.6 Mycobacterium Bovis.............................................................................................................. 91.7 Non-Tuberculous Mycobacteria............................................................................................. 102. Methods of Tuberculosis Screening............................................................................... 112.1 Definition of Active TB........................................................................................................... 112.2 Definition of Latent TB Infection .......................................................................................... 112.3 Tuberculin Skin Test............................................................................................................... 112.4 Factors Affecting the Result of the Tuberculin Skin Test....................................................... 152.5 Conversion and Boosting...................................................................................................... 162.6 Interferon-Gamma Release Assays (IGRA)............................................................................. 182.7 Interpretation of TST and IGRA Results................................................................................ 222.8 Chest X-Ray........................................................................................................................... 223. Management of Latent TB Infection.............................................................................. 263.1 Epidemiology of LTBI............................................................................................................. 263.2 Risk factors for LTBI............................................................................................................... 273.3 Selecting People for Treatment of LTBI................................................................................. 293.4 Treatment of LTBI................................................................................................................... 313.5 Treatment of Multidrug-Resistant or XDR LTBI..................................................................... 333.6 Pre-treatment Evaluation....................................................................................................... 343.7 Drug Regimens for LTBI......................................................................................................... 363.8 Risk of TB Associated with the Use of TNF- α Antagonists.................................................. 414. Laboratory Diagnosis of Tuberculosis............................................................................ 444.1 Role and Goals of the Modern TB Laboratory...................................................................... 444.2 Specimens.............................................................................................................................. 464.3 Specimen Processing............................................................................................................. 484.4 Processing of Positive Cultures............................................................................................. 514.5 False Positive Cultures........................................................................................................... 534.6 Interferon Gamma Release Assays (IGRA)............................................................................. 544.7 Laboratory Safety.................................................................................................................. 564.8 Quality Assurance.................................................................................................................. 585. Clinical Management..................................................................................................... 605.1 Diagnosis............................................................................................................................... 605.2 Supervision of TB Treatment................................................................................................. 625.3 Role of Public Health Staff in Clinical Management.............................................................. 635.4 Treatment of Tuberculosis...................................................................................................... 645.5 Inpatient or Outpatient Management................................................................................... 705.6 Adherence and Directly Observed Therapy (DOT)............................................................... 715.7 Legislation.............................................................................................................................. 736. Infection Prevention and Control.................................................................................. 746.1 Classification of Risk of Procedures in Healthcare................................................................. 746.2 Definition of an Infectious TB Case....................................................................................... 746.3 Administrative Aspects.......................................................................................................... 756.4 Standard Precautions............................................................................................................. 756.5 Airborne Precautions............................................................................................................. 766.6 Discontinuation of Airborne Precautions............................................................................... 84-iii-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC6.7 Discharging Patients with TB from Hospital.......................................................................... 846.8 Education............................................................................................................................... 867. BCG Vaccination............................................................................................................ 887.1 Clinical Efficacy...................................................................................................................... 887.2 Criteria for Discontinuation of a Universal BCG Vaccination Programme............................. 887.3 Dose and Route of Administration........................................................................................ 907.4 Indications for BCG Vaccine.................................................................................................. 907.5 Contraindictions.................................................................................................................... 917.6 Interactions............................................................................................................................ 927.7 Administration of BCG Vaccination....................................................................................... 927.8 Immunisation Reaction and Care of the Immunisation Site.................................................. 927.9 Adverse Reactions................................................................................................................. 927.10 Tuberculin Testing prior to BCG Immunisation...................................................................... 938. Contact Tracing............................................................................................................. 948.1 Factors Predicting TB Transmission....................................................................................... 948.2 Initiating the Contact Investigation....................................................................................... 968.3 Investigating the Index Case................................................................................................. 978.4 Prioritisation of Contacts....................................................................................................... 988.5 The Contact Tracing Interview............................................................................................... 998.6 Screening Tools.................................................................................................................... 1008.7 TB Outbreaks....................................................................................................................... 1058.8 Congregate Settings........................................................................................................... 1068.9 Workplaces.......................................................................................................................... 1068.10 Hospitals and other Healthcare Settings............................................................................. 1068.11 Schools ............................................................................................................................... 1088.12 Transportation...................................................................................................................... 1098.13 Prisons ............................................................................................................................... 1108.14 Other High Risk Settings..................................................................................................... 1118.15 Incorporating New Approaches to Contact Tracing........................................................... 1118.16 Evaluation of Contact Tracing.............................................................................................. 1128.17 Mycobacterium bovis.......................................................................................................... 1129. Screening in Special Situations................................................................................... 1139.1 Healthcare Workers............................................................................................................. 1139.2 New Entrants to Ireland....................................................................................................... 1179.3 Prisons, Remand and Detention Centres............................................................................ 1199.4 Homeless Individuals........................................................................................................... 12210. TB and HIV Infection................................................................................................... 12410.1 Epidemiology and Surveillance of TB Infection................................................................... 12410.2 Pathophysiology.................................................................................................................. 12410.3 Diagnosis of TB in HIV-infected Cases................................................................................ 12510.4 Diagnosis of HIV in TB Cases............................................................................................... 12610.5 Screening for LTBI................................................................................................................ 12610.6 Treatment of Active Disease................................................................................................ 12710.7 Treatment of LTBI in HIV-Positive Individuals...................................................................... 12710.8 Evaluation of a TB/HIV Case................................................................................................ 12810.9 Prevention and Control....................................................................................................... 13011. Education, Research and Information......................................................................... 13211.1 Education............................................................................................................................. 13211.2 Research.............................................................................................................................. 13211.3 Information.......................................................................................................................... 133REFERENCES ...............................................................................................................................134LIST OF APPENDICES................................................................................................................... 156GLOSSARY OF TERMS................................................................................................................. 188-iv-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCNational TB Advisory CommitteeDr Darina O’Flanagan (Chair)Health Protection Surveillance CentreDr Kevin Blake (Dr Ria Mahon up to December 2005)Irish Medicines BoardDr Colette BonnerDepartment of Health and ChildrenDr Eamon BreathnachFaculty of Radiology/Royal College of Surgeons in IrelandDr Karina ButlerFaculty of Paediatrics/Royal College of Physicians of IrelandDr Bartley CryanIrish Society of Clinical MicrobiologistsMs Nora CumminsCEO Representative (former Health Boards)Dr Fiona Donnelly (Dr Dominick Natin up to November 2005)Faculty of Occupational Medicine/Royal College of Physicians of IrelandDr Catherine FlemingInfectious Diseases Society of IrelandMs Grace Fraher (up to December 2007)Public Health Nurses RepresentativeMr Noel GibbonsAcademy of Medical Laboratory ScienceDr JJ GilmartinConsultant Respiratory Physician, Merlin Park Hospital, Galway/Irish Thoracic SocietyMs Margaret GoodDepartment of Agriculture, Fisheries and FoodDr Margaret Hannan (since February 2007)Consultant Microbiologist, Mater Misericordiae University Hospital, DublinDr Joseph KeaneConsultant Respiratory Physician, St James’s Hospital, Dublin/Irish Thoracic SocietyDr Brendan Keogh (since February 2007)Consultant Respiratory Physician, Mater Misericordiae University Hospital, DublinDr Timothy McDonnellConsultant Respiratory Physician, St. Vincent’s University Hospital, Dublin/Irish Thoracic SocietyDr Terry O’Connor (Member of Clinical Subgroup only)Consultant Respiratory Physician, Mercy University Hospital, CorkDr Joan O DonnellHealth Protection Surveillance CentreMs Ann O’Reilly-FrenchInfection Prevention Society-v-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCDr Margaret O’SullivanFaculty of Public Health Medicine/Royal College of Physicians of IrelandDr Heidi PellyCEO Representative (former Health Boards)Professor Tom RogersClinical Microbiologist, Director, Irish Mycobacteria Reference Laboratory, St. James’s Hospital, Dublin.Dr David ThomasIrish College of General PractitionersBCG Vaccination SubgroupDr Eibhlin ConnollyDepartment of Health and ChildrenDr Kevin ConnollyConsultant Paediatrician, National Immunisation Advisory CommitteeDr Brenda CorcoranNational Immunisation OfficeHPSC secretariatDr Lorraine HickeySenior Medical OfficerDr Abaigeal JacksonSurveillance ScientistMs Sarah JacksonSurveillance ScientistDr Paul KavanaghSpR in Public Health MedicineDr Deirdre MulhollandSpR in Public Health MedicineDr Kate O’DonnellSurveillance ScientistDr Mary O’MearaSpR in Public Health MedicineMs Sheila DonlonInfection Prevention and Control Nurse-vi-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTerms of Reference1. To review the guidance on prevention and control of tuberculosis in Ireland including:I. SurveillanceII. ScreeningIII. Preventive therapyIV. Clinical managementV. Laboratory diagnosisVI. BCG vaccinationVII. HIV infection and tuberculosis.2. To review the epidemiology of tuberculosis and provide advice as required to the Royal Collegeof Physicians of Ireland (RCPI) Immunisation Committee on the use of vaccines to prevent cases oftuberculosis.3. To act as a source of expert advice on tuberculosis when required to make interim recommendations.-vii-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCForewordTuberculosis remains a significant cause of morbidity and mortality worldwide. In 2008, an estimated 8.9to 9.9 million new cases and 1.7 million deaths were reported globally. In Ireland, the incidence of TBhas fallen significantly from a high of 230 notifications per 100,000 population in 1952 when records firstbegan to a low of 9.7 per 100,000 in 2001. The incidence has remained relatively stable since then with arate of 11.3 per 100,000 in 2007 and an incidence rate of 8.0/100,000 in the indigenous Irish populationin 2007.The HIV epidemic has had a significant impact on TB rates globally as individuals with TB and HIVinfection are more likely to develop active TB disease during their lifetime than those who are HIVnegative. Drug resistance, including multidrug-resistant TB and extensively drug-resistant TB togetherwith the increasing number of TB-HIV co-infected patients is also challenging TB control. The WorldHealth Organization proposes to reduce the global incidence of active TB to less than 1 case per millionpopulation by 2050 and thus eliminate TB as a global public health problem. This offers a challenge toimprove TB control in Ireland.The first guidelines for the management and control of TB in Ireland were published in 1996. All thesections from the original guidelines have been updated and a new section on infection prevention andcontrol has been added. The recommendations in these guidelines are based on a review of internationalliterature and an extensive consultation process with relevant professionals.I would like to thank all the members of the committee for their invaluable contribution to this report andalso to acknowledge the work and commitment principally of Dr Joan O’Donnell who was ably assistedby Ms Sheila Donlon, Dr. Lorraine Hickey, Dr. Abaigeal Jackson, Dr. Kate O’Donnell, Mr. Noel Gibbonsand Dr. Margaret O’Sullivan in producing this report.Dr. Darina O FlanaganChairperson, National TB Advisory Committee.February 2010-viii-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCKey Recommendations1 Epidemiology and Surveillance of TB in Ireland1.1 Case definitions specified by the European Commission should be applied for the purposes ofnotification and submission of data for epidemiological surveillance and disease control. These casedefinitions are available on the Health Protection Surveillance Centre (HPSC) website at www.hpsc.ie/hpsc/NotifiableDiseases/CaseDefinitions/ (section 1.4).1.2 Once a diagnosis of tuberculosis (TB) is either laboratory confirmed or strongly suspected on clinicalgrounds, the medical officer of health (MOH) should be notified by the clinical director of thelaboratory and/or clinician as soon as possible and ideally at the time of diagnosis (section 1.5).1.3 Reporting of outbreaks of TB is a mandatory requirement (section 1.5).1.4 Detailed surveillance information should be recorded on the national tuberculosis notificationdatabase (NTBSS) and submitted to the Health Protection Surveillance Centre (HPSC). It is plannedthat TB surveillance will be included in the Computerised Infectious Disease Reporting System (CIDR)(section 1.5).2 Methods of TB Screening2.1 The standard tuberculin skin test (TST) recommended for use in Ireland is the Mantoux 2TU/0.1mltuberculin PPD. Mantoux 10TU/0.1/ml tuberculin PPD is not recommended for use in Ireland (section2.3).2.2 In all cases, the TST (Mantoux test) should be administered intradermally (section 2.3).2.3 The TST (Mantoux test) result should be read within 48 to 72 hours of receiving the test. Thetransverse diameter of the area of induration (and not the erythema at the injection site) is measuredwith a ruler and the result recorded using millimetres (section 2.3).2.4 The TST (Mantoux test) should be used as the first line test for the diagnosis of latent TB infection(LTBI) in contacts of infectious TB cases and others considered to be at high risk of LTBI. Those withpositive TST results should be considered for Interferon Gamma Release Assay (IGRA) testing (section2.6). IGRA should be considered on a case-by-case basis in adults and children as per the generalrecommendations in section 8.7.2.5 IGRA tests should not be used in the first instance for the diagnosis of active TB disease. Appropriatemicrobiological and molecular investigations remain the gold standard for the diagnosis of active TBdisease (section 2.6).2.6 Chest X-ray is not considered the “gold standard” for the diagnosis of pulmonary TB (section 2.8).3 Management of Latent TB Infection3.1 The following groups should be prioritised for the treatment of LTBI: 1) Recent converters; 2) HIVpositiveindividuals; 3) Those aged less than 5 years; 4) Persons receiving immunosuppressive therapye.g. Tumour Necrosis Factor-α (TNF-α) antagonists; 5) Persons with evidence of old healed TBlesions on chest X-ray; 6) Foreign-born persons from countries of high TB endemnicity (≥ 40 casesof TB/100,000 population notified per year); 7) Homeless persons; 8) Intravenous drug users and 9)healthcare workers (HCWs) (section 3.3).-ix-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC3.2 For the treatment of LTBI in the groups outlined in 3.1, the following is recommended:3.2.1 Groups 1-5: LTBI treatment should be offered to those in all age groups3.2.2 Groups 6-8: LTBI treatment should be offered to all those aged ≤55 years if supervisedtherapy i.e. directly observed therapy (DOT) is available. Otherwise, it should be offered tothose aged ≤35 years. These groups should be closely monitored for isoniazid toxicity.3.2.3 Group 9: The age limit for LTBI treatment should be assessed on a case-by-case basis i.e.treat all HCWs where the risk of progression from LTBI to TB disease is high regardless ofage. Where the risk of progression is low, the upper age limit for LTBI treatment is ≤ 35years.3.2.4 For all other persons not mentioned above, the upper age limit for LTBI treatment shouldbe ≤35 years (section 3.3).3.3 Care should be taken when prescribing LTBI therapy for those with co-morbidities which increasethe likelihood of hepatoxicity (section 3.3).3.4 Directly observed therapy (DOT) should be provided for those being treated for LTBI in groups 6,7 and 8 i.e. immigrants from areas of high TB endemnicity, homeless persons and intravenous drugusers (section 3.4).3.5 It is recommended that audits of compliance with LTBI therapy are undertaken (section 3.4).3.6 The recommended treatment regimens for LTBI in adults are: (i) isoniazid for a minimum ofsix months with an optimum duration of nine months or (ii) rifampicin for four months or (iii) acombination of rifampicin and isoniazid for a duration of at least three months and an optimum offour months (section 3.4).3.7 The recommended treatment regimens for LTBI in children are: (i) isoniazid for a minimum ofsix months with an optimum duration of nine months or (ii) rifampicin for six months or (iii) acombination of rifampicin and isoniazid for a duration of four months (section 3.4).3.8 Physicians experienced in the management of children with LTBI should supervise therapy inchildren (section 3.4).3.9 Consultation with a respiratory physician or infectious disease consultant should be sought for themanagement of persons with active TB or LTBI who have been exposed to patients with MDR-TB orXDR-TB (section 3.5).3.10 Clinicians may choose to undertake baseline liver function tests (LFTs) for all patients aged over 14years at the start of treatment for LTBI. However, this is not universally obligatory (section 3.6).3.11 A consultant with expertise in TB should always be consulted when treating a patient with LTBI withdocumented hepatotoxicity (section 3.7).3.12 Breastfeeding is not a contraindication to LTBI therapy. Isoniazid or rifampicin are not secreted insufficient quantities in breast milk to harm the baby (section 3.7).3.13 Ideally monthly clinical monitoring (or at the discretion of the physician) is indicated for all patientson LTBI treatment (section 3.7).3.14 Prior to commencing TNF-α antagonists, patients should be thoroughly assessed by the treatingphysician for clinically active TB disease and for LTBI (section 3.8).-x-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC4 Laboratory Diagnosis of Tuberculosis4.1 It is a mandatory requirement for clinical directors of diagnostic laboratories to notify cases of activeTB disease to the MOH (director of public health (DPH) or designate) (section 4.1).4.2 Culture is necessary to achieve the “gold standard” for the diagnosis of active TB disease (section4.1).4.3 Microscopy and culture for TB should only be performed in those laboratories where there issufficient throughput to ensure proficiency (section 4.1).4.4 Laboratories should aim to meet the “goals” set down by CDC and others (section 4.1).4.5 All mycobacterial isolates should be referred to the Irish Mycobacteria Reference Laboratory (IMRL)for identification and susceptibility testing once its new facility is opened (section 4.1).4.6 All M. tuberculosis complex isolates should be referred to the IMRL with immediate effect formolecular typing where typing is now offered. (section 4.1).4.7 The results of all M. tuberculosis complex isolates which have already had identification,susceptibility and molecular typing performed should be forwarded to the IMRL for incorporationinto a national repository of M. tuberculosis complex isolates (section 4.1).4.8 Reasonable efforts should be made to obtain the best quality sample possible depending on thesite of disease and to deliver it in a timely fashion to the analysing laboratory (section 4.2).4.9 It is recommended that solid media is used in combination with a liquid culture system (section 4.3).4.10 All those wishing to undertake nucleic acid amplification tests (NAAT) on suspected cases ofpulmonary TB should seek advice from the local consultant microbiologist. It is recommended thatNAAT should be made available at the IMRL (section 4.3).4.11 Recommendations in the Seventh Schedule of S.I. 146/1994 Safety, Health and Welfare at Work(Biological Agents) Regulations 1994 should be interpreted as mandatory in relation to working withM. tuberculosis complex (section 4.7).4.12 All relevant legislation (national and international) for the transport and handling of specimens andcultures for TB should be strictly adhered to at all times (section 4.7).4.13 Laboratories should participate in internal and external quality assurance schemes for all testsperformed (section 4.8).5 Clinical Management5.1 All persons with an otherwise unexplained productive cough lasting three or more weeks with atleast one additional symptom, including fever, night sweats, weight loss or haemoptysis should beevaluated for TB. This will include clinical, radiological and bacteriological examinations (section5.1).5.2 All cases of suspected active TB should be referred to a TB clinic and have a clinical assessmentat the next available clinic. If immediate evaluation is required, consult with the clinical teamregarding the need for more urgent clinical assessment. The management of suspect TB cases canbe undertaken in collaboration with the clinical team (respiratory or infectious diseases) who willadvise on sputa collection and the clinical management (including commencement of therapy, if thesputa are positive for acid-fast bacillus (AFB)), until the next clinic appointment (section 5.1).5.3 Treatment of TB should be directed by a consultant respiratory physician/consultant in infectiousdiseases with appropriate training in the management and treatment of TB (section 5.2).-xi-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC5.4 There should be active case management with a dedicated case manager or health careprofessional who liaises with and follows the patient during the entire treatment course to monitorand enhance adherence (section 5.3).5.5 More widespread establishment of combined clinics attended by both respiratory physiciansand public health doctors for the diagnosis and treatment of TB (and LTBI) and the evaluationof contacts is recommended. Such clinics should be appropriately staffed with medical, nursing,pharmacy, administrative staff and medically qualified interpreters and should be integrated withthe hospital system (section 5.3).5.6 Isoniazid and rifampicin, with pyrazinamide and ethambutol for the initial two months (intensivephase), followed by isoniazid and rifampicin for a further four months (continuation phase)is recommended in patients with sensitive strains of tuberculosis and where there are nocontraindications (section 5.4).5.7 Six months of chemotherapy is usually adequate for the treatment of active disease caused bysensitive strains. However, it should be extended to nine months for the following patients:5.7.1 Patients with drug-susceptible pulmonary TB with initial cavitation on chest X-ray andwhose sputum cultures remain positive after the intensive phase ( i.e. the first two monthsof treatment)5.7.2 Other patients who are still culture positive at two months regardless of chest X-ray results5.7.3 Patients whose treatment regimen did not include pyrazinamide in the intensive phase orwhose organism is resistant to pyrazinamide5.7.4 Patients being treated with once weekly isoniazid and rifampicin whose sputum cultureremains positive after the two month intensive phase of treatment (section 5.4).5.8 Follow-up sputum specimens for smear and culture should be obtained monthly in patients withdrug-susceptible pulmonary disease. Requests for more frequent testing should only be undertakenfollowing discussion between the treating physician and consultant microbiologist. For patients withisoniazid- and rifampicin-susceptible TB there is no need to examine sputum monthly once cultureconversion is documented (i.e. two negative cultures taken at least two to four weeks apart). It isrecommended that identification and sensitivities are repeated in cases who are still culture positiveat ≥ two months (section 5.4).5.9 To enhance compliance and to minimise potential problems from the development of drugresistance, it is strongly recommended that only combination tablets should be used wheneverpossible (section 5.4).5.10 It is recommended that the supraregional TB centre at St James’s Hospital and a number of regionalcentres should have a small number of non-acute beds available to facilitate the inpatient care ofpatients who are non-compliant or have drug-resistant TB (section 5.5).5.11 Prioritising the establishment of a structured national DOT programme is recommended for moreeffective management and control of TB (section 5.6).6 Infection Prevention and Control6.1 Patients with known or suspected pulmonary or laryngeal TB should be admitted to an airborneisolation room (negative pressure isolation room with an ante room or a neutral pressure design asoutlined in HBN 04 supplement 1). Hospitals need to have a risk assessment process to ensure theappropriate provision of isolation facilities (section 6.5).-xii-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC6.2 All patients with suspected or known pulmonary or laryngeal TB must have a risk assessment forMDR-TB (section 6.5).6.3 Patients with suspected or confirmed MDR-TB must be admitted to an airborne isolation room(negative pressure isolation room with an ante room or a neutral pressure design as outlined inHBN 04 supplement 1). (This may require transferring the patient to another institution where thefacilities, together with a physician experienced in the management of complex drug-resistant casesare available) (section 6.5).6.4 Healthcare Workers (HCWs) (including HCWs visiting a patient in their own home) should wearFFP2 masks when caring for patients with suspected or confirmed infectious TB where MDR-TB orXDR-TB is not suspected. These patients are usually non-infectious after a minimum of two weekstreatment. The supervising clinician should be consulted before the use of masks is discontinued(section 6.5).6.5 HCWs should wear FFP3 masks when undertaking cough-inducing procedures on all patients (fullysusceptible and resistant strains included) e.g. sputum induction, bronchoscopy, administrationof aerosolised medications, airway suctioning, endotracheal intubation, caring for patients onmechanical ventilation and during treatment of lesions/abscesses when aerosolisation of drainagefluid is anticipated (section 6.5).6.6 HCWs (including HCWs visiting a patient in their own home) should wear FFP3 masks when caringfor patients with suspected or confirmed infectious MDR-TB or XDR-TB. The supervising clinicianshould be consulted before the use of masks is discontinued (section 6.5).6.7 A respiratory protection programme should be provided for all HCWs who may be required touse respiratory masks during the course of their work. HCWs should be fit tested by a trainedprofessional as part of this programme. All HCWs should fit check each time a mask is donned(section 6.5).6.8 Patients should wear a surgical mask while they are infectious when they are outside their room e.g.visiting the X-ray /OPD departments (section 6.5).7 BCG Vaccination7.1 The continuation of a universal programme of neonatal BCG vaccination is recommended in Irelandat this time (section 7.2).7.2 When BCG is given to infants there is no need to delay the primary immunisations. No furtherimmunisation should be given in the arm used for BCG immunisation for at least three monthsbecause of the risk of regional lymphadenitis (section 7.3).7.3 Training for health professionals in the correct administration of BCG vaccine is recommended.Those administering vaccine should be aware of indications, contraindications, immunisation andadverse reactions associated with BCG (section 7.4).7.4 BCG should not be administered to an individual with a positive tuberculin (or interferon-gamma)test (section 7.10).8 Contact Tracing8.1 Contact tracing should be conducted according to the concentric circle approach, whereby contactswith greatest exposure to the index case are prioritised for screening (chapter 8).8.2 Infectious pulmonary and laryngeal cases are priorities for contact investigation. A precautionaryapproach should be taken with broncheoalveolar lavage (BAL) smear positive cases (section 8.1).-xiii-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC8.3 Those BAL smear positive cases with cavitation on chest X-ray, MDR-TB or XDR-TB or wherecontacts are immunosuppressed or less than 5 years of age should be presumed infectious forcontact tracing purposes (section 8.1).8.4 The determination of infectivity of all other BAL smear positive patients should be considered on acase-by-case basis (clinical/microbiology/public health input) (section 8.1).8.5 Young children under 10 years of age with pulmonary disease are rarely infectious. Such contacttracing investigations should be focused on finding a source and co-primary cases (section 8.1).8.6 The recommended interval between first and second screening rounds (TST ± IGRA) in contactinvestigations is eight weeks. If the last contact with the infectious case exceeded an eight-weekperiod, one TST is sufficient (section 8.6).8.7 Contact tracing of infectious or potentially infectious TB cases on aircraft should be limited toflights which were ≥8 hours duration and took place during the previous three months. All cases ofrespiratory TB who are sputum smear positive and culture positive (if culture available) are deemedinfectious. All cases of respiratory TB who are sputum smear negative and culture positive aredeemed potentially infectious. The following criteria should also be used when determining theinfectiousness of a case at the time of travel: (i) presence of cavitations on chest X-ray, (ii) presence ofsymptoms at the time of the flight and (iii) documented transmission to close contacts (section 8.12).8.8 If the index case is a passenger, obtain contact details of passengers sitting in the same row andthe two rows ahead and behind (from one side of the aircraft to the other because of ventilationpatterns) the index patient. Inform contacts of possible exposure and advise screening of thesecontacts and of cabin crew who serviced the section in which the TB case was seated (section 8.12).8.9 If the index case is an aircraft crew member, contact tracing of passengers should not routinelytake place. Contact tracing of other members of staff is appropriate, in accordance with the usualprinciples for screening workplace colleagues (section 8.12).8.10 A multidisciplinary team approach to effectively manage TB contact tracing in prisons is required.The team should be led by the local public health department who will undertake contact tracing(section 8.13).8.11 DOT is recommended for all prisoners receiving treatment for active disease and should beconsidered for those receiving treatment for LTBI (section 8.13).8.12 Evaluation of all contact tracing activities is recommended. The following information should becollected: (a) number of contacts identified (b) number of cases of active disease and LTBI and (c)the number of persons who accepted and completed preventive therapy (section 8.16).9 Screening in Special Situations9.1 A pre-placement screen is recommended for all clinical staff working with patients or clinicalspecimens (this may also be applicable to ancillary staff, as determined by a risk assessment)(section 9.1).9.2 If an employee has unexplained and suggestive symptoms such as cough lasting three or moreweeks that is unresponsive to usual interventions and weight loss or fever, a chest X-ray and sputumexamination should be carried out. Such employees should not start work. If an employee has nosuspicious symptoms, completion of the pre-placement questionnaire should be followed by anappropriate medical evaluation (section 9.1).9.3 HCWs from countries of high TB incidence (≥ 40 cases of TB per 100,000 per year) with a positiveTST (Mantoux test) defined as ≥10mm (table 2.1) should be referred to a respiratory or infectious-xiv-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC-xvdiseaseclinician (with a chest X-ray) for a medical assessment to rule out TB disease or LTBI.However, an occupational medicine consultant may wish to treat these patients if appropriateprotocols, audit of care and resources are in place (section 9.1).9.4 Irish HCWs or HCWs from low incidence countries (< 40 cases of TB per 100,000 per year) with apositive TST (Mantoux test) defined as ≥15mm should be referred to a respiratory or infectiousdisease clinician (with a chest X-ray) for a medical assessment to rule out TB disease or LTBI.However, an occupational medicine consultant may wish to treat these patients if appropriateprotocols, audit of care and resources are in place (section 9.1).9.5 All new entrants to Ireland who originate from a country with a high incidence of tuberculosis (≥40cases per 100,000 population per year) and will be spending at least three months in Ireland shouldbe provided with an opportunity to be screened for TB (section 9.2).9.6 An expanded programme of screening for TB including voluntary screening for HIV in new entrantsshould be established. The committee believes that this should be part of a broader healthscreening programme to improve the health of new entrants to Ireland (section 9.2).9.7 A programme of screening for TB in prisoners should be provided (section 9.3).9.8 Prisoners should receive chemotherapeutic treatment for active disease or LTBI by DOT, as highrates of treatment failure have been observed in this population. Patients undergoing any formof TB treatment should be assigned a key worker (a health professional) to promote compliance,monitor treatment effectiveness and the occurrence of adverse events (section 9.3).9.9 Prison medical services should liaise with community TB services to ensure the continuation of DOTafter release from prison (section 9.3).9.10 An opportunistic active case finding strategy is advised among homeless individuals. Screening bychest X-ray is recommended. TST and IGRA are believed to be less useful, as people may movebefore test reading /results are available (section 9.4).9.11 Nomination of a key worker for homeless patients receiving treatment and the provision of DOTare considered an optimal strategy for treatment completion (section 9.4).10 Tuberculosis and HIV Infection10.1 Cases of TB/HIV should always be managed by physicians with expertise in treating both TB andHIV (chapter 10).10.2 A high index of suspicion should be maintained for TB in all HIV-infected individuals (section 10.1).10.3 In HIV-infected individuals, routine screening for TB is advisable. HIV-infected children should bescreened annually for TB, beginning at age three to 12 months (section 10.5).10.4 All TB cases should be offered HIV testing (section 10.4).10.5 The recommended treatment regimens for LTBI in adults who are HIV positive are: (i) isoniazidfor an optimum duration of nine months or (ii) rifampicin for four months or (iii) a combination ofrifampicin and isoniazid for four months (section 10.7).10.6 The recommended treatment regimens for LTBI in children who are HIV positive are: (i) isoniazid fora minimum of six months with an optimum duration of nine months or (ii) rifampicin for six monthsor (ii) a combination of rifampicin and isoniazid for four months (section 10.7).10.7 DOT is recommended for the treatment of all HIV-infected TB cases (section 10.7).

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC11 Education, Research and Information11.1 Given the increased importance of LTBI and TB diagnosis and treatment: TB education in theundergraduate and postgraduate medical/nursing/pharmacy disciplines needs to be strengthened(section 11.1).11.2 Research that seeks to improve our understanding of the pathobiology of TB as well as the natureof the disease in our country is to be encouraged; research funding agencies should foster suchactivity which has potential to improve the treatment of the disease both locally and internationally(section 11.2).11.3 Studies to determine the prevalence rate of LTBI should be initiated and supported (section 11.2).-xvi-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAbbreviationsACDP Advisory Committee on Dangerous Pathogens (UK)AFBAcid Fast BacilliAIDSAcquired-Immune Deficiency SyndromeALTAlanine TransaminaseASAspartate TransaminaseATSAmerican Thoracic SocietyBALBronchoalveolar LavageBCGBacille Calmette-GuérinBHIVA British HIV AssociationCDCCenters for Disease Control and PreventionCFCystic FibrosisCIDRComputerised Infectious Disease Reporting SystemCL3 Containment Level 3CNSCentral Nervous SystemCOSHH Control of Substances Hazardous to Health (UK Regulations)CPA (UK) Clinical Pathology Accreditation Ltd (UK)CPHM Consultant in Public Health MedicineCXRChest X-rayDOTDirectly Observed TherapyDOTS Strategy Directly Observed Therapy Short-course StrategyDPHDirector of Public HealthEEthambutolECEuropean CommissionECDC European Centre for Disease Prevention and ControlELISA Enzyme-Linked Immunosorbent AssayEUEuropean UnionEuroTB European Network for Surveillance of TBFDAFood and Drug Administration (USA)HIsoniazidHAART Highly Active Antiretroviral TherapyHCWHealthcare WorkerHIVHuman Immunodeficiency VirusHPSCHealth Protection Surveillance CentreHRZThree-Drug Regimen: Isoniazid, Rifampicin and PyrazinamideHSEHealth Service ExecutiveIATAInternational Air Transport AssociationIGRAInterferon-gamma release assayIL-1Interleukin-1-xvii-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCIMRLIRISISTCIUATLDLFTsLHOLIPLTBIMACMDGMDR-TBMOHMTCNAATNEQASNICENTBSSNTMOCTPGLPPDRSGOTSGPTSISMOSSITBTNF-αTSTUKUSAWHOXDR-TBZZNIrish Mycobacteria Reference LaboratoryImmune Reconstitution Inflammation SyndromeInternational Standards of TB CareInternational Union against TB and Lung DiseaseLiver Function TestsLocal Health OfficeLymphoid Interstitial PneumoniaLatent TB InfectionMycobacterium avium ComplexMillennium Development GoalMultidrug-Resistant TBMedical Officer of HealthMycobacterium tuberculosis ComplexNucleic Acid Amplification TestsNational External Quality Assessment Service (UK)National Institute of Clinical Excellence (UK)National TB Surveillance SystemNon-tuberculous MycobacteriaOutbreak Control TeamPersistent Generalised LymphadenopathyPurified Protein DerivativeRifampicinSerum Glutamic Oxaloacetic TransaminaseSerum Glutamate Pyruvate TransaminaseStatutory InstrumentSenior Medical OfficerStatens Serum Institut (Denmark)TuberculosisTumour Necrosis Factor-αTuberculin Skin TestUnited KingdomUnited States of AmericaWorld Health OrganizationExtensively Drug-Resistant TBPyrazinamideZiehl Neilson-xviii-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC1. Epidemiology and Surveillance of TuberculosisHumanum tuberculosis (TB) is caused by infection with bacteria of the Mycobacterium tuberculosis complex(M. tuberculosis, M. bovis, M. africanum, M. microti, M. canetii, M. caprae or M. pinnipedii). The organismmay infect any part of the body. However, the majority of cases involve the respiratory system.1.1 Global TrendsTB remains a significant cause of morbidity and mortality worldwide. An estimated 9.3 million new caseswere reported in 2007, of which 7.8 million were detected in Asia and Africa. Of the 9.3 million new cases,1.4 million (15%) were co-infected with human immunodeficiency virus (HIV). Approximately 1.8 milliondeaths occurred due to TB, of which 456,000 individuals were co-infected with HIV, accounting for 25% ofthese deaths. Worldwide, the incidence of disease is stable, although case numbers particularly in Africa,South-Eastern Asia and Eastern Mediterranean countries continue to rise. 1 In 1993, the World HealthOrganization (WHO) declared TB a ‘global emergency’ in response to a resurgence in cases, followingnearly a century of decline. 2 To improve control, targets for TB control recommended by WHO’s WorldHealth Assembly 3 were defined within the United Nations Millennium Development Goals (MDG 6, target8), and indicators to measure progress towards these goals were proposed by the Stop TB partnership in2006. 4;5Table 1.1: Indicators of progress towards Millennium Development Goals 5STOP TB PARTNERSHIP TARGETS• By 2005: At least 70% of new sputum smear positive TB cases will be detected and atleast 85% of these cases cured• By 2015: Reduce prevalence of and death due to TB by 50% relative to 1990• By 2050: The global incidence of active TB will be less than 1 case per millionpopulation (i.e. elimination of TB as a global public health problem).The HIV epidemic has had a significant impact on TB rates. Individuals with TB and HIV infection are morelikely to develop active TB disease during their lifetime than those who are HIV negative, making HIV themost potent predictor of progression to active TB. 4;6 Drug resistance, including multidrug-resistant TB(MDR-TB) and extensively drug-resistant TB (XDR-TB) (see table 1.2), together with an increasing numberof TB-HIV co-infected patients is challenging TB control.Table 1.2: Definitions of drug resistanceDRUG RESISTANCE DEFINITIONS• Multidrug-resistant TB (MDR-TB): TB bacilli resistant to at least isoniazid and rifampicinwith or without resistance to ethambutol and streptomycin• Extensively drug-resistant TB (XDR-TB): is resistance to at least isoniazid and rifampicin(i.e. MDR-TB), plus resistance to any fluoroquinolone, and any one of the followingsecond line anti-TB injectable drugs (capreomycin, amikacin or kanamycin).Incomplete and incorrect treatment regimens may result in patients remaining infectious, and bacilli intheir lungs may develop resistance to anti-TB medicines. While drug-resistant TB is generally treatable,it requires extensive chemotherapy (for up to two years) that is often prohibitively expensive (often more-1-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCthan 100 times more expensive than treatment of drug susceptible TB) and is also more toxic to patients.Recent findings from a survey conducted by WHO and the US Centers for Disease Control and Prevention(CDC) on data from 2000-2004 found that XDR-TB has been identified in all regions of the world butwas most frequent in the former Soviet Union and in Asia. 7 A recent outbreak of XDR-TB in HIV-infectedindividuals in South Africa highlighted a worrying situation whereby 52 of 53 XDR-TB patients died within amedian of 16 days. 81.2 Tuberculosis in EuropeIn European countries, the decline of TB in the latter half of the twentieth century was accelerated by acombination of improved socioeconomic conditions such as better housing and reduction of overcrowdingand biological factors e.g. improved nutrition, advent of chemotherapeutic drugs, BCG immunisationprogrammes. 9 However, in the last decade overall rates in the WHO European region began to increasesteadily from 28 notifications per 100,000 population in 1994 to 54 notifications per 100,000 populationin 2007. 10 Disparities in rates between Western and Eastern European countries are apparent and havediverged further in recent years. The incidence of disease in the Eastern European region (comprisingmostly of states of the former Soviet Union) continues to increase annually and in 2007 rates in excess of131 cases per 100,000 population were reported. Former Soviet Union countries have the greatest burdenof disease and the highest rates of multidrug-resistance and mortality rates ranging from 3.0 to 22.3 deathsper 100,000 population. This region remains a priority for TB control. 10The Western European region (European Union and Western European countries) reported a rate of 17cases per 100,000 population in 2007. This region experienced a steady decrease in overall TB incidencefor a number of decades, briefly reversed in certain countries in the early 1990s. 11 This pattern was also firstobserved in the United States of America during the 1980s and early 1990s due in part to the impact ofHIV but also due to the problems of homelessness, drug abuse, immigration from high incidence countriesand deterioration in living conditions and health care delivery to the poor. 12 A concerted effort to controlTB in the US resulted in a 45% reduction in cases and halved the incidence rate to 5 cases per 100,000population between 1992 and 2002.In low-incidence European countries, specific challenges to TB control have emerged as a result of thisshift from high to low incidence. 13 These include a declining incidence in native populations, the increasingimportance of LTBI, disease in immigrant populations, groups at high risk (HIV-infected, homeless andprisoners) and importation of drug resistance (e.g. multidrug-resistance from Eastern Europe and othercountries). In the United Kingdom, national rates have remained low overall but have gradually increased inEngland by 25% (1994-2004). 14 The London region accounted for the highest proportion of cases in 2007at 41% of all UK cases notified and had the highest TB notification rate at 44.8 per 100,000. Most TB casescontinue to occur in young adults (61% were aged 15-44 years) and in the non-UK born population (72%). 15In 2004, an action plan entitled ‘Stopping Tuberculosis in England’ 16 was published by the UK Departmentof Health, to focus efforts on controlling increasing TB levels.In 1996, a European network for surveillance (EuroTB) was introduced, based on the participation ofnational TB surveillance institutions in the 53 countries of the WHO European Region. Its aims were toimprove the contribution of surveillance to TB control in the WHO European region, through the provisionof valid, comparable epidemiological information on TB. Annual reports indicate that Cyprus had thelowest notification rate of disease in 2007 in the 27 EU countries (EU-27) at 5.3 cases per 100,000, whileIreland ranked in sixteenth position (table 1.3).-2-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 1.3: Notification and mortality rates per 100,000 reported by EuroTB 10 for all 27 EU countries:2007, 2006.Country Notification rate per 100,000 (2007) Mortality rate per 100,000 (2006)Cyprus 5.3 0.26Sweden 5.4 naFinland 5.9 1.14Greece 5.9 0.73Netherlands 5.9 0.46Germany 6.1 0.53Denmark 7.2 0.17Luxembourg 8.1 0.00Malta 9.3 0.25Italy 7.6 naFrance 8.8 naCzech Republic 8.4 0.51Austria 10.5 0.68Slovenia 10.8 0.90Belgium 9.7 naIreland 10.9 0.94Slovakia 12.6 naUnited Kingdom 13.8 0.79Spain 17.3 naHungary 17.4 naPoland 22.6 1.99Portugal 29.5 0.21Estonia 36.3 4.99Bulgaria 39.8 3.51Latvia 55.1 7.95Lithuania 71.3 10.87Romania 118.3 7.89Total all EU countries 17.0 na(na: not available)1.3 Tuberculosis in IrelandFollowing the introduction of compulsory notification of all forms of TB in 1948, declining rates ofmorbidity and mortality were observed in Ireland throughout the latter half of the twentieth century 17(figure 1.1). The first national survey of TB in Ireland reported 6,795 notifications in 1952, giving anotification rate of 230 cases per 100,000 population. 18 A downward trend was sustained until 2001 (381cases, 9.7 per 100,000 population) after which case rates became stable, with minor fluctuations in annualfigures thereafter. In 2006, there were 465 cases of TB notified in Ireland, representing a rate of 11.0 per100,000 population. 19 Mortality rates also declined, from 266 per 100,000 population in 1901 18 to 0.94 per100,000 in 2006, and are now amongst the lowest reported in Western Europe. 10 The majority of deathsfrom TB now occur in those aged 65 years and older.-3-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC80007000600050004000300020001000019521953195419551956195719581959196019611962196319641965196619671968196919701971197219731974197519761977197819791980198119821983198419851986198719881989199019911992199319941995199619971998199920002001200220032004200520062007RespiratoryNon-respiratoryFigure 1.1: TB cases notified to the Department of Health and HPSC, 1952-2006 (breakdown byrespiratory /non-respiratory not available for 1994) 19Geographical distributionConsiderable variation exists in TB notification rates between HSE areas in Ireland (table 1.4). Overall,annual incidence rates in HSE areas fluctuate, with no discernable increasing/decreasing pattern in anyregion. HSE South (Cork and Kerry) typically reports the highest annual crude case rate, with rates rangingbetween 12.4 and 15.3 per 100,000 between 2000 and 2006. Since 2000, case rates have remained above10 per 100,000 in both HSE East and HSE South (Cork and Kerry), and consistently below 10 per 100, 000in HSE Midlands and HSE Northwest. This distribution differs from that documented in the 1950s when theproportion of the population with pulmonary disease in Dublin was nearly twice that in any other area inIreland. 18 In 2006, the largest number of notifications was reported by HSE East (193 notifications). 19In Northern Ireland, 62 cases were notified in 2006, and since 1990, an incidence rate of 3 to 5 cases per100,000 population per year has been recorded. 15Table 1.4: Crude TB incidence rates per 100,000 population by HSE area, 1992-2006 19HSE E HSE M HSE MW HSE NE HSE NW HSE SE HSE S HSE W Total1992 16.1 18.7 20.9 10 15.9 12.3 21.4 22.2 17.11993 11.9 10.8 16.1 10 37.5 16.7 23.9 23 171994 12.9 14.6 17.3 11.4 9 11 17.4 22.7 14.51995 11.9 8.8 15.1 8.5 11.4 9.5 20.5 11.1 12.61996 8.7 8.3 17.7 12.1 7.1 6.9 22.5 13.1 121997 9.9 9.2 12.6 9.1 10.4 12.8 16.5 11.1 11.51998 11.7 4.9 14.8 9.5 9 8.9 14.3 15.3 11.71999 13.9 7.3 17 8.2 9 7.9 13.7 19.9 12.92000 10.2 7.1 13.8 6.1 4.1 9.7 13.8 10 10.12001 12.3 3.1 7.1 11 5.9 4.7 12.4 8.9 9.72002 11.6 8.4 9.4 7 5.4 11.6 13.3 8.7 10.42003 11.9 5.3 12.4 7.5 4.1 8.3 16 6 10.42004 12.6 3.6 12.2 5.8 6.7 7.4 11.8 10.6 10.22005 13 6.4 14.7 3.3 6.3 8 12.2 10.9 10.62006 12.9 6.0 10.2 8.4 3.8 11.1 15.3 7.7 11.0-4-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAge and sexAs in other developed countries, more TB cases are notified annually in males than females in Ireland andthe rate is consistently higher in males across all age groups. There were 280 (60.2%) notifications for malesin 2006, giving a male to female ratio of 1.5:1. The median age of cases was 45 years (range 0 to 93 years)in 2006. As reflected in other European countries, the majority of foreign-born cases occur in younger agegroups. In 2006, the majority (83.2%) of foreign-born cases occurred in those aged 15 to 44 years (median31 years). Over one-third (39.1%) of Irish cases occurred in persons aged 55 years and older in the sameyear. 19Ethnicity and place of birthSince 1998, the number of foreign-born cases has tripled, while Irish born case numbers have declinedoverall. In 2006, the crude rate of TB in the indigenous population was 8.3 per 100,000 and 26.3 per100,000 in the foreign-born. Approximately, two-thirds (63.2%) of all cases notified in 2006 were Irish born.Of those born outside Ireland, 37% were born in Asia and 36% in Africa. 19Drug resistanceBetween 2001 and 2006, 10 to 27 cases per annum were resistant to at least one front-line anti-TB therapy.Of these an average of two cases had MDR-TB. In 2006, four cases of MDR-TB were reported. 19 In 2005,the first reported case of XDR-TB was detected in Ireland. 201.4 Surveillance of TBClinical notification of TB was introduced in 1948 17 and the Infectious Diseases Regulations 1981 asamended by the Infectious Diseases (Amendment) (No. 3) Regulations 2003 (S.I. No. 707 of 2003)extended the scope of this legislation. 21 From 2004, it became mandatory for clinical directors oflaboratories to notify a case of TB to the regional director of public health (DPH) under their role as medicalofficer of health (MOH). 21The 2003 amendment also made reporting of outbreaks a mandatory requirement. 21 The legislationdescribes outbreaks as “an unusual cluster or changing pattern of illness” which is defined as anaggregation of health events, grouped together in time or space that is believed or perceived to begreater than could be expected by chance. This may apply to a geographic area, facility or a specificpopulation group. This definition relates to cases of TB disease only and not to cases of LTBI. LTBI is not anotifiable disease.Case definitionsA decision of the European Commission (Decision No. 2002/253/EC) specified the case definitions tobe applied by Member States for the purposes of submitting data for the epidemiological surveillanceand control of communicable disease. 22 In April 2008, the above decision was amended (Decision No.2008/426/EC) updating these case definitions. 23 The updated standardised European case definitions areused for notification of TB in Ireland (table 1.5). 23-5-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 1.5: EU standardised case definitions for notification of a TB case 23TUBERCULOSIS (Mycobacterium tuberculosis complex)Clinical CriteriaAny person with the following two:• Signs, symptoms and/or radiological findings consistent with active tuberculosis in any siteAND• A clinician’s decision to treat the patients with a full course of anti-tuberculosis therapyOR• A case discovered post-mortem with pathological findings consistent with active tuberculosisthat would have indicated anti-tuberculosis antibiotic treatment had the patient beendiagnosed before dying.Laboratory CriteriaLaboratory criteria for case confirmationAt least one of the following two:• Isolation of Mycobacterium tuberculosis complex (excluding Mycobacterium bovis-BCG)from a clinical specimen• Detection of M. tuberculosis complex nucleic acid in a clinical specimen AND positivemicroscopy for acid-fast bacilli or equivalent fluorescent staining bacilli on light microscopy.Laboratory criteria for a probable caseAt least one of the following three:• Microscopy for acid-fast bacilli or equivalent fluorescent staining bacilli on light microscopy• Detection of M. tuberculosis complex nucleic acid in a clinical specimen• Histological appearance of a granuloma.Epidemiological Criteria: Not applicable.Case ClassificationPossible case: Any person meeting the clinical criteriaProbable case: Any person meeting the clinical criteria and the laboratory criteria for aprobable caseConfirmed case: Any person meeting the clinical criteria and the laboratory criteria for aconfirmed case.Recommendation:Case definitions specified by the European Commission should be applied for the purposesof notification and submission of data for epidemiological surveillance and disease control.These case definitions are available on the Health Protection Surveillance Centre (HPSC)website at www.hpsc.ie/hpsc/NotifiableDiseases/CaseDefinitions/.Patients with pulmonary TB are further subdivided into sputum smear positive and sputum smear negativecases.-6-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCSputum smear positive TBThe revised WHO definition of a new sputum smear positive pulmonary TB case is based on the presenceof at least one acid fast bacillus (AFB+) in at least one sputum sample in countries with a well functioningexternal quality assurance (EQA) system in their laboratories. 24Sputum smear negative TBA sputum smear negative patient has:• At least three negative sputum smears (including at least one early morning specimen)• Chest X-ray findings consistent with TB and• Lack of response to a trial of broad-spectrum antimicrobial agents (Note: because thefluoroquinolones are active against M. tuberculosis complex and thus may cause transientimprovement in persons with TB, they should be avoided). 25It should be noted that in making a diagnosis of sputum smear negative TB based on the above threecriteria, a clinician who decides to treat with a full course of anti-TB chemotherapy should report thisas a case of sputum smear negative pulmonary TB to the MOH. Although the results of culture maynot be available until after a decision to begin treatment has to be made, treatment should be stoppedsubsequently if cultures are negative, the patient has not responded clinically and the clinician has soughtother evidence in pursuing the differential diagnosis. 25TB outbreaksThe following are examples of situations to report:1. An unexpected increase (significantly above baseline) of newly identified confirmed or suspectedcases in any setting2. Two or more TB cases on treatment from a congregate (e.g. school or prison) or high risk settinge.g. HIV positive individuals occurring within a relatively short space of time3. Three or more TB cases on treatment in a household4. Three or more cases on treatment from a community setting (outside a household) occurring withina relatively short period of time who may be related5. Two or more cases of MDR-TB or XDR-TB that may be related and occur outside a household.When assessing whether a cluster of TB cases represents an outbreak, indicators to look for include:• Epidemiological links between cases• Similar unique characteristics among cases• Matching drug resistance patterns of isolates• Matching DNA fingerprint patterns of isolates.Outbreaks of particular concern are MDR-TB or XDR-TB outbreaks, outbreaks among immunocompromisedpopulations, children or other vulnerable groups.1.5 Notification ProceduresOnce a diagnosis of TB is either laboratory confirmed or strongly suspected on clinical grounds, the MOHshould be notified by the clinical director of a diagnostic laboratory and/or clinician as soon as possibleand ideally at the time of diagnosis (appendix 2). Infection prevention and control staff or other laboratorymedical or scientific staff to whom the function of providing notification of infectious diseases has beendelegated by the clinician/clinical director of the laboratory may notify the case (s) also if authorised to doso by the clinician. Notification should be made using the infectious disease notification form available at:www.hpsc.ie/hpsc/NotifiableDiseases/NotificationForms/.-7-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCOnce notified, the MOH or designated medical officer, usually a Consultant in Public Health Medicine(CPHM) shall inform the designated members of the contact tracing team of cases of new and re-treatmentTB as they occur. Immediate notification enables prompt contact tracing and facilitates successful contactinvestigation. The practitioner notifying presumed cases of TB is also required to inform the MOH ordesignated medical officer if the diagnosis subsequently proves not to be TB. If the case of TB is fromanother HSE area, the MOH or designated medical officer should notify his/her opposite number in therelevant HSE area. The responsible MOH is required to report possible, probable and confirmed cases ofTB to the Health Protection Surveillance Centre (HPSC).Recommendation:Once a diagnosis of TB is either laboratory confirmed or strongly suspected on clinicalgrounds, the MOH should be notified by the clinical director of the laboratory and/or clinicianas soon as possible and ideally at the time of diagnosis.In the case of unusual incidences or clusters of TB cases, they should be notified by the MOH ordesignated medical officer to the HPSC as they occur. 21Recommendation:Reporting of outbreaks of TB is a mandatory requirement.Following notification of a case of TB, the MOH or designated medical officer shall seek further clinicaldata on the case as an aid to contact tracing and detailed TB surveillance. The national TB notificationform is available at: http://www.hpsc.ie/hpsc/AZ/VaccinePreventable/TuberculosisTB/SurveillanceForms/(appendix 3).Enhanced surveillanceThe specific objectives of surveillance are to:• Support local management of identified cases, contacts and screening programmes• To monitor the incidence and distribution of TB disease at both local and national level• To identify risk factors to support interventions aimed at the prevention of TB• To monitor the process and outcome of disease control and screening programmes so thatimprovements can be introduced• To monitor antibiotic susceptibility to M. tuberculosis and M. bovis to guide appropriate use ofantibiotics.Notification of cases of TB forms the basis of surveillance and public health follow-up of cases and contacts.The early identification of cases of TB is essential to the effective management and control of the disease.National epidemiological data on TB have been collated by the HPSC, formerly the National DiseaseSurveillance Centre (NDSC) since 1998. Prior to the establishment of HPSC, limited epidemiologicaldata had been collated for TB in Ireland. An enhanced national TB surveillance system (NTBSS) becameoperational in 2000, following consultation with the eight health boards and the National TuberculosisAdvisory Committee. The NTBSS is based on the minimum dataset required to be reported by Ireland toEuroTB, 10 the European TB surveillance centre located at the European Centre for Disease Prevention andControl (ECDC), which collates national TB data within Europe and contributes epidemiological data to theWHO global TB control programme for Europe.-8-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTB notification forms summarise all available clinical, microbiological, histological and epidemiologicaldata (see appendix 3). Forms collated in regional departments of public health are anonymised andsubmitted electronically to HPSC for the production of reports on a quarterly basis. HSE areas makequarterly returns to HPSC of TB notifications (which consist of disaggregate data on new TB notifications)in their area six weeks after the end of each quarter. Data in quarterly reports are provisional until aprocess of validation has been completed at the end of that notification year. At the end of each yearand early into the following year, information on all cases is updated and validated by each HSE areato include outcome data. Annual reports are generally produced eighteen months after the end of thenotification year to allow for the collection of complete treatment outcome information. Annual nationalTB reports are accessible at: www.hpsc.ie/hpsc/A-Z/VaccinePreventable/TuberculosisTB/Publications/AnnualReportsontheEpidemiologyofTBinIreland/.It is proposed to incorporate the enhanced TB surveillance system into the Computerised InfectiousDisease Reporting (CIDR) system in the future. CIDR is an integrated surveillance system providinglaboratory and clinical data. This should lead to more complete and timely data on the epidemiology of TBin Ireland.Recommendation:Detailed surveillance information should be recorded on the national tuberculosis notificationdatabase (NTBSS) and submitted to HPSC. It is planned that TB surveillance will be included inthe Computerised Infectious Disease Reporting (CIDR) system.1.6 Mycobacterium BovisTB due to M. bovis infection accounts for a very small proportion of cases of locally acquired TB inIreland and consequently there is no evidence that zoonotic TB is a major public health problem inIreland at present. However, when it does occur, infection with M. bovis may produce a clinical pictureindistinguishable from that caused by other members of the M. tuberculosis complex. The individualspecies within the complex cannot be distinguished from each other based on microscopic examination ofstained tissues or other clinical specimens.The majority of individuals are thought to have a very low risk of M. bovis infection but possibleoccupational exposures may occur in those in close contact with animals or animal carcasses such asfarmers, veterinary practitioners and others who work with animals or their products or those consuminghome produce such as unpasteurised milk on farms. Certain groups of people such as the very young,elderly people or people with suppressed immune systems may be particularly vulnerable.Programmes for the early detection and elimination of M. bovis-infected cattle represent a safeguardagainst exposures and in particular milk borne transmission of M. bovis, by ensuring the elimination ofinfected animals from milk-producing herds. All cattle herds are required to have an annual test for TBon the animals within the herd, each year approximately 10 million animal tests are carried out (personalcommunication, Department of Agriculture, Fisheries and Food). This level of testing ensures that thereis little opportunity for the development of advanced cases of TB in cattle, thus minimising the possiblesource of infection for humans. The risk from occupational and food borne infection is therefore now verylow. The risk is further reduced in Ireland by the present requirement that all milk intended for sale andsupply for human consumption, with the exception of milk for preparation of certain types of cheese, mustbe pasteurised.Unquestionably, contaminated milk was a major source of human infection with M. bovis until recentdecades. As the principal route of human food borne infection with M. bovis is via ingestion rather thanby inhalation, infection of the tonsils, cervical lymph nodes, gastrointestinal tract, genitourinary infectionand TB of the bones and joints has been considered to be associated with M. bovis. 26 Over 75% of thoseinfected are now aged fifty years and over, suggesting the reactivation of latent infection acquired early in-9-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSClife (personal communication, HPSC). Although there is much less complete information available for otheranimal species, infection with M. bovis does occur in other species of domestic and wild animals includinggoats, badgers and deer. 261.7 Non-Tuberculous MycobacteriaSpecies of mycobacteria other than M. tuberculosis complex are pathogenic to humans. Often the clinicalpresentation of non-tuberculous mycobacteria (NTM) is similar to that caused by M. tuberculosis complex.In the past, NTM was not often responsible for clinical disease but infections due to NTM are increasinglyobserved in immunocompromised individuals. A study in the Southwest of Ireland reported that themean incidence of NTM has risen since 1995 (0.4/100,000 population), principally due to pulmonaryMycobacterium avium intracellulare complex (MAC). 27-10-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC2. Methods of Tuberculosis ScreeningDiagnosis of active or latent TB involves a number of tests. There is no gold standard for determiningwhether a person is infected with M. tuberculosis but in practice the tuberculin skin test (TST) is thestandard method used. Recently immunological blood tests i.e. interferon-gamma release assays (IGRA)have been developed to aid diagnosis. However, neither the TST nor IGRA can be used to distinguishlatent infection from active disease.2.1 Definition of Active TBActive TB is defined as infection with mycobacteria of the M. tuberculosis complex, where mycobacteriaare growing and causing symptoms and signs of disease. This is distinct from LTBI where mycobacteriaare present but are inactive and not causing symptoms of disease. The diagnosis of active TB is mademost often on the basis of positive bacteriology but in approximately 15%-25% of cases on the basis ofappropriate clinical and/or radiological and/or pathological presentation as well as treatment response (seechapters 4 and 5).2.2 Definition of Latent TB InfectionA person with LTBI usually has a positive TST or IGRA test but has no physical findings of TB disease andthe chest X-ray is normal or only reveals evidence of healed infection i.e. granulomas or calcification in thelung, hilar lymph nodes or both. Persons with LTBI are asymptomatic and are not infectious (see table 3.1,chapter 3).The three screening methods discussed in this chapter are:1. Tuberculin skin test2. Interferon-Gamma Release Assays (IGRA)3. Chest X-ray.2.3 Tuberculin Skin TestThe main tool to diagnose TB infection is the TST. It is also used as an aid to the diagnosis of active TBdisease. In Ireland, the Mantoux test is the TST used. This test consists of the intradermal injection of asmall amount of purified protein derived from Mycobacterium tuberculosis bacteria (PPD). The local skinreaction to PPD is used to assess an individual’s sensitivity to the tuberculin protein. In a person who hascell-mediated immunity to these tuberculin antigens, a cell-mediated delayed hypersensitivity reaction willoccur within 48 to 72 hours. The reaction will cause localised swelling and will be manifest as induration ofthe skin at the injection site. The greater the reaction, the more likely it is that an individual is infected orhas active TB disease. In persons who are newly exposed and become infected with TB, this cell-mediatedreaction to tuberculin will develop 3 to 8 weeks later. 28WHO recommends that the Mantoux 2TU/0.1ml tuberculin PPD should be used and this is the standardtest recommended for use in Ireland. A comparative study undertaken by Comstock et al revealed that2TU has almost identical sensitivity to the use of 5TU for tuberculin testing although specificity was slightlylower with 2TU. 29 However, it was concluded that the results of testing with 2TU and 5TU were sufficientlysimilar to deem them biologically equivalent. 29Recommendation:The standard tuberculin skin test (TST) recommended for use in Ireland is the Mantoux2TU/0.1ml tuberculin PPD. Mantoux 10TU/0.1ml tuberculin PPD is not recommended for usein Ireland.In general testing for LTBI is indicated when the risk of development of disease is increased if the patient isinfected.-11-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCThere are three general situations when the disease risk is increased:• Recent infection: most commonly contacts of a patient with a recent diagnosis of infectious TBdisease or immigrants or persons from countries of high TB incidence (≥40 per 100,000 TB casesnotified per year) within 2 years of arrival in Ireland• Increased risk of reactivation due to impaired immunity: This includes HIV infection andimmunosuppressed conditions e.g. diabetes, renal failure, immunosuppressant medications andpulmonary silicosis• When there is radiological evidence of old, healed inactive TB but no prior treatment. 30The following persons should not receive a TST:• Those who had severe blistering TST reactions in the past or with extensive burns or eczemapresent over TST testing sites, because of the greater likelihood of adverse or severe reactions• Those with documented active TB disease or a well-documented history of adequate treatment forTB infection or disease in the past. In such patients the test is of no clinical utility.• Those with major viral infections e.g. varicella (chickenpox), measles, mumps, infectiousmononucleosis BUT not the common cold or minor viral infections• Those who received MMR vaccines in the previous four weeks as this has been shown to increasethe likelihood of false negative TST results. No data are available in relation to the effect of otherlive virus vaccines e.g. varicella or yellow fever but it would be prudent to follow the same fourweek guidance. 30The following persons can receive a TST:• Those with a common cold• Those who are pregnant or breastfeeding• Those immunised with any vaccine on the same day• Those immunised within the previous 4 weeks with inactivated vaccines• Those who give a history of a positive TST reaction (other than blistering) that is not documented• Those taking low doses of systemic corticosteroids, < 15mg prednisolone (or equivalent) daily. Itgenerally takes a steroid dose equivalent to ≥15mg prednisolone daily for 2-4 weeks to suppresstuberculin reactivity. 30;31Administration of the Mantoux testIn all cases, the Mantoux test should be administered intradermally. This is also sometimes referredto as intracutaneous administration. The Mantoux test is normally performed on the flexor surface ofthe left forearm at the junction of the upper third and the lower two-thirds. If the skin is visibly dirty, itshould be washed with soap and water. The Mantoux test is performed using a 0.1ml tuberculin syringeor alternatively a 1ml graduated syringe fitted with a short bevel 26G (0.45x10mm) needle. A separatesyringe and needle must be used for each subject to prevent cross-infection. Then 0.1ml of PPD should bedrawn into the tuberculin syringe and the 25G or 26G short-bevelled needle attached to give the injection.The needle should be firmly attached and the intradermal injection administered with the bevel facinguppermost.The operator stretches the skin between the thumb and forefinger of one hand and with the other handslowly inserts the needle with the bevel upwards for about 5mm into the superficial layers of the dermisalmost parallel to the surface. The needle can usually be seen through the epidermis. A correctly givenintradermal injection results in a tense blanched raised bleb and considerable resistance is felt when thefluid is being injected. A bleb is typically of 7mm diameter following a 0.1ml intradermal injection. If littleresistance is felt when injecting and a diffuse swelling occurs rather than a tense bleb the needle is toodeep and should be withdrawn and reinserted intradermally on the opposite forearm or on the sameforearm at a site at least 10cm away from the previous injection. Do not cover the site with a bandage.Inform the patient that he or she should not scratch the site but may perform all normal activitiesincluding showering or bathing. Record the following details: a) date of injection; b) dose (2TU, 0.1ml);c) manufacturer; d) lot number; e) expiry date; f) site of injection and g) person who administered theinjection.-12-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCDetailed instructions on performing a Mantoux test are available on the National Immunisation Officewebsite at www.immunisation.ie/en/Downloads/PDFFile_14983_en.pdf.Similar instructions are also available on the Staten Serum Institut (Denmark) website at www.ssi.dk/sw11710.asp.Recommendation:In all cases, the TST (Mantoux test) should be administered intradermally.StorageCare should be taken to store PPD Mantoux tests and BCG vaccine in separate areas of the fridge toensure the correct product is administered. If using the vial of Tuberculin PPD (Mantoux) on more than onepatient, it is recommended that once the vial is in use, it should be used immediately. Otherwise it shouldnot be in use for longer than 24 hours and stored between 2 and 8°C as per Tuberculin PPD productspecific details from Statens Serum Institut (SSI) in Copenhagen. 32 In light of the need for the immediateuse of the vial of PPD as indicated above, it is recommended that where possible a clinic should bearranged to undertake Mantoux testing on more than one person.Reading the TST (Mantoux test)The TST should be read by a trained health professional. Individuals without experience in reading a TSTmay not feel slight induration and the result may be mistakenly recorded as 0mm.TST interpretation depends on a number of factors as follows:• Measurement of the induration in millimetres• The person’s risk of being infected with TB and of progression to disease if infected• Prior BCG vaccination or exposure to non-tuberculous mycobacteria (NTM) (section 2.4)• Conditions resulting in a false negative result (section 2.4).The results should be read within 48 to 72 hours of receiving the test but a valid reading can usually beobtained up to 96 hours later. The transverse diameter of the area of induration and not the erythemaat the injection site is measured with a ruler and the result recorded using millimetres. As several factorsaffect interpretation of the test, the size of the induration should be recorded and NOT just as a positive ornegative result.It is recommended that the following items are recorded:• Date the induration was read• Measurement of the induration if any in millimetres• Any adverse reactions e.g. blistering (can occur in 3-4% of subjects) and• The name of the individual who read the test.There is some variability in the time at which the test develops its maximum response. The majority oftuberculin-sensitive subjects will be positive at the recommended time of reading. The predictive value canbe enhanced by using cut-off points dependent on the infection risk. The reaction to a TST is classified aspositive based on the individual’s risk factors (see table 2.1). In general, a negative TST result is ≤ 5mm. Forthe interpretation of TST results in contact tracing situations and in screening of HCWs and new entrants,see chapters 8 and 9.-13-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendation:The TST (Mantoux test) result should be read within 48 to 72 hours of receiving the test. Thetransverse diameter of the area of induration (and not the erythema at the injection site) ismeasured with a ruler and the result recorded using millimetres.Note:• A delay in reading the TST if the result is positive i.e. >5mm does not affect the validity of theresults• A strongly positive TST resulting from inadvertent subcutaneous administration does not affect thevalidity of the reading.Deciding that a TST is positiveThe health professional reading the TST must decide whether the test result is positive. This is based onthe size using the criteria listed in table 2.1. Once a TST is considered positive the individual should bereferred for a medical evaluation. There is no clinical utility in performing a TST in the future once a testthat was properly performed and read is considered positive. 30Medical evaluationThis should include assessment of symptoms suggestive of possible active TB, risk factors for TB such ascontact history or other medical illness and a chest X-ray. In the event of symptoms or an abnormal chestX-ray, sputum for acid-fast bacteria smear and culture should be taken. In persons with no evidence of TBdisease, treatment of LTBI should be considered.-14-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 2.1: Categories of response to TSTs (Mantoux tests) based on individual’s risk factor(s) fordevelopment of TB disease 33 ᴪAn induration of>5mm is consideredpositive in:An induration of ≥10mm is consideredpositive in:An induration of ≥15mm is consideredpositive in:• HIV-infected persons• A recent contact of a person with active TB disease• Persons with fibrotic changes on chest X-ray consistent with prior TB and nodocumented treatment• Persons with organ transplants and other immunosuppressed persons e.g.those taking the equivalent of ≥15mg/day of prednisolone for one month orlonger or taking TNF-alpha antagonists• Children aged < 5 years (with no BCG) from a country with a high incidenceof TB (≥ 40/100,000 per year)• Immigrants: Persons (aged 16 to 35 years) who have immigrated within thepast 5 years from countries with a very high TB incidence (>500/100,000) andchildren aged 5 to 15 years who have immigrated (within the past 5 years)from countries with TB incidence ≥40/100,000 per year• All children

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCMenzies and Doherty 36 state that although all recipients of BCG will have positive tuberculin reactionswithin two months of vaccination with BCG, these reactions will wane over time. Studies by Menzies et al(1992, 1994) indicate that for those vaccinated with BCG in infancy, only 3-5% manifest a positive TST whentested 5 years after the vaccination. 37;38 This may reflect the relative immaturity of the immune system ininfants although protective efficacy if anything is higher. 39;40 Of those vaccinated at an older age, tuberculinreactions are larger and wane more slowly. In this older cohort, on average 30-35% will have BCG-relatedpositive TST results even after an interval of more than 10 to 15 years. 37-39;41-43 Post-BCG vaccination canaccount for up to 10mm of induration, and there is no published evidence to suggest that this sensitivitycorrelates with immunological protection. 44-47Note:Care should be taken when attributing BCG vaccination as a cause of a positive TST if: 30• BCG vaccine was given in infancy and the person tested is now aged 10 years or older• There is a high probability of TB infection i.e. close contacts of an infectious TB case or immigrants(including HCWs) from countries with high annual TB incidence (see table 2.1)• There is a high risk of progression from TB infection to disease (see table 3.2)• Any TST ≥15mm induration should not be attributed to BCG vaccination.False negative TST resultsThe reaction to tuberculin protein may be suppressed by the following:• Cutaneous anergy (anergy is the inability to react to skin tests because of a weakened immunesystem)• Recent TB infection (within eight to 10 weeks of exposure)• Old TB infection• Age: very young age (less than three months old) and the elderly• Major viral infections e.g. varicella (chickenpox), measles, mumps, infectious mononucleosis• Recent live viral vaccination e.g. measles, mumps, rubella, varicella and yellow fever (tuberculintesting should not be undertaken within four weeks of having received a live viral vaccine)• Malnutrition, particularly when there has been recent weight loss 48• Extensive TB disease (pulmonary or miliary) can itself also temporarily depress immunity and canlead to a paradoxically negative TST 49• Other illnesses e.g. malignancies especially lymphoma, renal failure, sarcoidosis, diabetes mellitus• Immunosuppression due to disease including HIV infection• Immunosuppression due to treatment including cytotoxics, corticosteroid therapy (≥15mgprednisolone daily for four weeks or longer), transplant therapy and infliximab• Incorrect method of TST administration. 50 This should be avoidable.• Incorrect interpretation of the TST reaction• Insufficient dose of PPD• Inactive tuberculin PPD: tuberculin PPD vials must be used within 24 hours of opening.Subjects who have a negative test but who may have had one of the major viral infections (excluding thecommon cold) outlined above at the time of testing or at the time of reading the test should be re-testedtwo to three weeks after clinical recovery before being given BCG.2.5 Conversion and BoostingA newly positive TST after an initial negative test result and an increase of > 5mm represents a truebiological phenomenon in two consecutively performed TSTs. This could be due to conversion or boosting.-16-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCConversionConversion is defined as the development of new hypersensitivity to mycobacteria following exposure tonew TB or NTM infection including BCG vaccination. 36 A conversion is presumptive evidence of new M.tuberculosis infection and poses an increased risk for progression to TB disease indicating a change frombeing uninfected to infected. 51Conversion is more likely in a previously tuberculin negative individual or in a situation of high risk ofexposure to TB such as in a close contact of a sputum smear positive index case or in an outbreakinvestigation. If a person who has a documented negative TST result within the previous 12 months isexposed to an infectious TB case, then only one TST (Mantoux test) is necessary to detect conversion.Persons who demonstrate TST conversion should be investigated for active disease or LTBI. 36BoostingBoosting is defined as the recall of non-specific immunity in the absence of new infection and is mainlyseen in adults and older persons. 36 When non-specific or remote sensitivity to tuberculin (PPD in the skintest) wanes or disappears with time, subsequent tuberculin skin tests can restore the sensitivity. 51 An initiallylimited reaction size is followed by a larger reaction size on a later test, which can be confused with aconversion or a recent M. tuberculosis infection. If an increase in reaction size is noted after one to threeweeks and there has been little or no possibility of exposure then it is likely that the increase is due toboosting. 51 Boosting is best distinguished from conversion on clinical grounds.Two-step testingTwo-step testing is used to distinguish new infections from boosted reactions in infection control andprevention surveillance programmes. This method is not recommended for testing contacts of infectiousTB cases. A contact whose second test result is positive after an initial negative result should be classifiedas recently infected. 51In persons who may be liable to boosting in whom it is important to establish a true baseline TST response,a second TST can be administered one to three weeks after the first. The second test should be doneon the other arm; repeat testing at one site may alter the reactivity either by hypo- or more often hypersensitisingthe skin and a changed response may only reflect local changes in skin sensitivity. The resultof the second boosted reaction is the correct result, that is the result which should be used for decisionmaking and future comparison. This two-step approach can reduce the likelihood that a boosted reactionto a subsequent TST will be misinterpreted as recent infection.Two-step testing is indicated in the following situations when the first TST (Mantoux test) in thetwo-step series is negative:(a) Where serial tuberculin tests are to be used as in HCWs; and(b) When tuberculin testing those with previous BCG vaccination, this does not apply to contactsof infectious cases who will already have been re-sensitised when transmission has occurred. 33;52If the second test is positive (table 2.1), it is recommended that the individual is referred for medicalevaluation including a chest X-ray and they should not undergo further tuberculin testing. If the chest X-rayis normal and there are no associated factors that increase the risk of TB reactivation, then preventivetherapy is not indicated.The two-step test needs to be performed once only if properly performed and documented. It never needsto be repeated. Any subsequent TST can be one step regardless of how long it has been since the lastTST. 30-17-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC2.6 Interferon-Gamma Release Assays (IGRA)In recent years in-vitro immunological assays called IGRA have been developed to diagnose TB infection.These assays involve a single blood test and operate on the basis that T-cells which have been in previouscontact with TB antigens release high levels of the cytokine interferon gamma when they are re-exposedto the same mycobacterial antigens. 53 This reaction is specific to a small number of mycobacteria includingM. tuberculosis but not to the BCG vaccine strain of M. bovis and consequently are less influenced by priorBCG vaccination than TSTs. The amount of interferon gamma or the number of M. tuberculosis sensitiveT-cells in the blood is then estimated by the tests. T-cells which have not been in contact with the bacteriumwill not release cytokine. 54There are currently two IGRA assays commercially available for use: QuantiFERON-TB Gold® In –Tube(Cellestis Ltd., Australia) and T-SPOT.TB (Oxford Immunotec) (see chapter 4).QuantiFERON-TB Gold® In –Tube assay measures the release of interferon gamma in whole blood inresponse to stimulation by ESAT 6 and CFP 10. In the T-SPOT.TB test, individual activated ESAT 6, CFP 10and TB 7.7 specific T-cells are enumerated using the ELISPOT methodology. It has been suggested that theT-SPOT.TB test may be more sensitive than QuantiFERON-TB Gold® In –Tube in children under five yearsof age and in immunocompromised patients. 55BInternational guidelines on the use of IGRAIn 2005, CDC recommended that the Food and Drug Administration (FDA)-approved version ofQuantiFERON-TB Gold® In –Tube assay may be used in place of the TST for all indications includingcontact tracing and serial testing of healthcare workers. 56;57 In 2007, an updated version QuantiFERON-TBGold® In –Tube was approved for this function. In 2006, the UK National Institute for Health and ClinicalExcellence (NICE) guidelines recommended a hybrid two-step approach for LTBI diagnosis; initial screeningwith TST and subsequent IGRA testing (if available) for those who are TST positive (or in whom TST may beunreliable) to confirm TST results. 26Evidence from international studies suggests that IGRA have a higher specificity than tuberculin skin testsand have less potential for false positive results. 26;58;59 Both IGRA are very specific (93% to 99%) and areunaffected by prior BCG. While several QuantiFeron studies have consistently shown very high specificity,data are limited on the specificity of the commercial T-SPOT.TB assay. 60 A number of systematic reviewshave been published which support this view. 54 The results of a meta-analysis carried out in 2007 however,is not so clear cut. While both IGRA tests were more specific than TSTs when applied to all patients, thedifference between IGRA and TST disappeared when patients known to have BCG vaccine were excluded.Both IGRA tests were more sensitive than TST with the T-SPOT.TB assay displaying higher sensitivity (~90%)60 61compared to the QuantiFERON-TB Gold® (approximately 75% to 80%).Use of IGRA also showed little evidence of being affected by prior BCG vaccination and strongercorrelation with exposure categories than did tuberculin skin tests. This was shown in low prevalencegroups, in household contacts and in outbreak situations. 62;63 A recent study on the use of TST versusIGRA for the diagnosis of LTBI in a HCW population in Germany concluded that TST overestimates theprevalence of LTBI in HCWs and recommended that a positive TST result should be verified by IGRA.However, they also concluded that more studies are required in order to confirm that IGRA are moresensitive in diagnosing LTBI than the TST. 64 In conclusion, from the evidence, it is currently justifiable toassume that IGRA are at least as sensitive as TST and more specific in populations that include previouslyBCG vaccinated individuals.The results of a limited number of studies, published to date, assessing the predictive value of IGRA areinconclusive. A recent German study found that 14.6% of IGRA positive individuals developed active TBcompared to 5.6% of TST positive contacts. 65-18-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendations for the use of IGRAIGRA use should be considered in conjunction with a clinical and public health risk assessment. If available,IGRA can be used for the diagnosis of LTBI in the following settings.Contact tracing (see chapter 8)• The TST (Mantoux test) should be used as the first line test for the diagnosis of LTBI in contactsof infectious TB cases and others considered to be at high risk of LTBI. Those with positive TSTresults should be considered for IGRA testing, if available (see figures 8.1 & 8.2)• IGRA may be considered on a case by case basis in adults and children as per the generalrecommendations in section 8.7. 60Pre-placement screening of HCWsIn new HCWs who are asymptomatic for TB and have a low pre-test probability of LTBI, IGRA, if available,can be used to confirm a positive TST result. Persons with a positive IGRA should be considered fortreatment of LTBI (see chapter 9).New entrant screeningAlthough the use of IGRA in screening new entrants has not clearly been demonstrated to date, the use ofIGRA can be considered:• As a confirmatory test in those individuals with a positive TST• In screening new entrants with concomitant conditions that increase the individual’s risk ofreactivation of LTBI (chapter 9).For individuals commencing on immunosuppressive therapy, i.e. tumour necrosis factor-α (TNF-α)antagonists.• IGRA, if available, can be used as an adjunct to screening in addition to a medical history, chestX-ray and TST.IGRA, if available, can be considered as the sole test for LTBI in the situation outlined below:• When screening large numbers of individuals as part of a public health investigation where logisticissues make repeated visits for sequential testing impractical. 54Recommendation:For contact tracing, the TST (Mantoux test) should be used as the first line test for thediagnosis of LTBI in contacts of infectious TB cases and others considered to be at high risk ofLTBI. Those with positive TST results should be considered for IGRA testing (see figures 8.1 &8.2). IGRA may be considered on a case by case basis in adults and children as per the generalrecommendations in section 8.7. 60IGRA performance in immunocompromised populationsThere are few studies on the sensitivity and specificity of IGRA in immunocompromised populations. TSTsensitivity is modest to poor in these populations. The sensitivity of T-SPOT.TB appears to be maintainedin immunocompromised individuals and appears to have a higher rate of positivity than TST. QuantiFeronstudies have not demonstrated this. 60 In the immunocompromised person (adult or child), the TST shouldbe the initial test used to detect LTBI. If the TST is positive, the person should be considered to have LTBI.However, in light of the known problem of false negative TST results in immunocompromised populations,a clinician still concerned about the possibility of LTBI in an immunocompromised person with an initialnegative TST result may perform an IGRA test. If the IGRA test is positive, the person might be consideredto have LTBI. If the IGRA result is indeterminate, the test should be repeated to rule out laboratory error.If the second test is negative, the clinician should suspect anergy and rely on the person’s history, clinical-19-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCfeatures and other laboratory results to make a decision on the likelihood of LTBI. Either IGRA test may beused, however, there is evidence that the T-SPOT.TB assay may be more sensitive that the QuantiFeron testand this will be especially relevant for immunocompromised populations. 60While the approach of accepting either test result (TST or IGRA) as positive will improve the sensitivityof detecting LTBI in immunocompromised populations, there are no data supporting the efficacy ofpreventive therapy in TST negative but IGRA positive individuals. Thus the clinician must weigh thepotential benefit of detecting more persons with positive test results against the lack of evidence for thebenefit of preventive therapy in such persons.Potential boosting of IGRA by previous TSTPrevious guidelines by CDC state that the results of IGRA are not influenced by previous TST. 51 Studiesby Leyten et al 66 and Richeldi et al 67 report no boosting phenomenon following the evaluation of T-SPOT.TB assay. Some studies however, have reported boosting of the QuantiFERON-TB Gold® In –Tube assayresults when taken 6 to 8 weeks after a TST. 68;69 Although these studies have limitations, there are animalstudies suggesting that TST might boost subsequent measurements of interferon gamma. 70;71 This issuerequires further investigation. Due to these concerns, it is recommended by both the HPA and the PublicHealth Agency of Canada that the IGRA test should be undertaken at the time of reading the Mantouxresults. 54;60Serial testingThere are insufficient data to inform recommendations on serial testing with IGRA. Studies of serial testingof individuals with either LTBI or TB disease do not show a clear pattern. In some studies, IGRA responsesincreased, 72 decreased 73 or showed no change. 74 Further studies are needed.Diagnosis of active TB diseaseIGRA should not be used in the first instance for the diagnosis of active TB disease in either adults orchildren and should not replace the appropriate microbiological and molecular investigation.Culture remains the gold standard for the diagnosis of TB disease as it provides a definitive diagnosis andpermits the identification of drug resistance. IGRA have no benefits in known pulmonary TB cases withbacteriological/molecular confirmation.Recommendation:IGRA tests should not be used in the first instance for the diagnosis of active TB disease.Appropriate microbiological and molecular investigations remain the gold standard.However, in some patients (adults and children) with TB, it is not possible to isolate M. tuberculosis fromclinical specimens or to obtain clinical specimens, despite the individual having symptoms, signs and/or radiological changes consistent with the diagnosis of TB. In these circumstances, a positive IGRA mayincrease confidence in the diagnosis. In those with symptoms or signs compatible with but not indicativeof the diagnosis of TB, a positive IGRA test may suggest more strongly the possibility of a TB diagnosis. 54However, the final decision should be based on clinical judgment. 54 60 IGRA tests cannot distinguishbetween active TB and LTBI. 60Advantages of IGRA tests• It only requires one visit from the patient compared to two visits for a TST• IGRA demonstrate improved specificity over the TST i.e. the proportion identified as disease freeand the reduced cross-reactivity with BCG vaccine and most NTM means that persons are less-20-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSClikely to have unnecessary treatment for presumed LTBI if they are correctly identified as diseasefree• IGRA are at least as sensitive as the TST. 75Limitations of IGRA tests• Some patients may find a blood test less acceptable than an intradermal test• The TST is cheaper than IGRA• Logistical issues may arise, as the laboratory must receive the blood sample within 8 hours for theT-SPOT.TB test and within 16 hours for QuantiFERON-TB Gold® In-Tube assay. 75Recommendations on IGRA use are based on the best currently available scientific evidence and medicalpractice. Over time, if new evidence emerges in relation to IGRA, this will be reviewed by the committeeand the recommendations revised if deemed appropriate.-21-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC2.7 Interpretation of TST and IGRA ResultsUse of the following table (from the Public Health Agency of Canada) 60 is recommended for theinterpretation of TST and IGRA results:Table 2.2: Interpretation of results when both TST and IGRA results are availableRisk of developing TB disease if infected with M. tuberculosis **HighLowIGRApositiveIGRAnegativeIGRAindeterminateIGRApositiveIGRAnegativeIGRAindeterminateTST+veConsider treatment for LTBIConsidertreatment forLTBITreatment forLTBI is notnecessaryRepeat IGRA test or baseinterpretation on TSTresultTST-veConsidertreatmentfor LTBILTBItreatmentnot necessaryif immunocompetentRepeat IGRAtest or baseinterpretation onTST resultConsult TBspecialistTreatment for LTBI not necessarySource: Updated recommendations on interferon gamma release assays for latent TB infection. Canada Communicable DiseaseReport, Public Health Agency of Canada (October 2008). Reproduced with the permission of the Minister of Public Works andGovernment Services Canada, 2009. Available at www.phac-aspc.gc.ca/publicat/ccdr-rmtc/08pdf/acs-6.pdf.** See table 3.3 in chapter 3 for risk factors for the development of active TB disease among persons with LTBINote:• This table is offered in the context of the IGRA recommendations above and is not meant to be acomprehensive guide to the management of LTBI. See chapter 3 for the management of LTBI andfor groups at risk of developing active TB disease (table 3.3)• IGRA are more specific in populations that include previously BCG vaccinated individuals andhence would be very useful in the Irish context as it would lead to a decrease in false positiveresults.2.8 Chest X-RayChest X-Ray for the diagnosis of LTBIChest radiography is not usually considered a tool to diagnose LTBI. Its main role is in the diagnosis of TBdisease. However, it is quite common that a chest X-ray is done for some other reason and radiographicabnormalities consistent with previous TB infection are detected. Individuals are considered to haveinactive TB or LTBI when their chest X-ray shows certain abnormalities consistent with TB infection ANDthey have a positive TST result (table 2.1). These individuals have an increased risk for reactivation and maybe considered for treatment of LTBI (chapter 3).-22-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCThe following radiographic findings are commonly believed to represent latent/inactive TB. Whilesome are associated with increased risk of reactivation of active TB disease in future, others arenot.• Granulomas that may be calcified or not: this doubles the risk of reactivation resulting inactive TB disease• Calcified hilar lymph nodes: if there are no parenchymal lesions, these individuals do notappear to have an increased risk relative to those who are TST positive and have normalchest X-rays• Costophrenic angle blunting: this is due to past pleural effusion or pleurisy which may havemany causes. The most common cause in individuals from countries with high TB incidenceand other TB-endemic areas is previous exposure to Mycobacteria tuberculosis. Suchindividuals have an increased risk of reactivation• Apical pleural capping: this is not considered to be related to TB infection and is a nonspecificfinding that is more common in older individuals• Apical fibronodular disease: this is associated with increased risk of reactivation rangingfrom 6 to 19 times greater than those who are TST positive and have normal chest X-rays.Individuals with more extensive abnormalities have greater risk of disease. 30Source: Canadian Tuberculosis Standards, 6 th Edition. Public Health Agency of Canada, 2007. Reproduced with the permission of theMinister of Public Works and Government Services, 2009. Available at www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdfChest X-ray for the diagnosis of TB diseaseChest radiography [posterior-anterior (PA)] 76 is the usual first step in the evaluation of an individual withpulmonary symptoms. Additional views may be ordered at the clinician’s discretion. It is also recommendedthat patients suspected of having extrapulmonary TB have a chest X-ray to rule out pulmonary disease.In all instances, if the chest X-ray results are abnormal (including pleural TB), sputum samples should becollected on 2 to 3 separate days and tested for acid fast bacilli (AFB) (smears) as well as for culture anddrug susceptibilities.The radiological findings usually seen on chest X-ray for both immunocompetent and immunosuppressedadults are outlined below. However, it is important to be aware that chest X-ray has substantial limitationsin the diagnosis of pulmonary TB disease.Typical findings: a triad of classic findings are seen in immunocompetent adultsPosition- apical-posterior segments of upper lobes or superior segment of lower lobes in 90%Volume loss- this is a hallmark of TB disease as a result of its destructive and fibrotic natureCavitation- this is seen at a later stage and depends upon a vigorous immune response. Therefore,it may not be seen in severely immunocompromised individuals.Atypical features:These will be seen in patients with immunocompromising conditions such as HIV infection,diabetes, renal failure or corticosteroid use.Hilar and mediastinal lymphadenopathy, particularly in HIV-infected individualsNon-cavitary infiltrates and lower lobe involvement-23-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRadiographic signs of complications:Endobronchial spread of disease. TB may spread via airways to the ipsilateral and contralaterallower lobes. This results in irregular poorly defined small nodular shadows which represent acinarshadows. These will slowly enlarge and coalesce to form TB pneumonia, formerly known as“galloping consumption”Pleural effusion can be seen concomitant with pulmonary disease and may represent TBempyemaPneumothorax can rarely occur as a result of erosion of a caseous focus into a bronchus andsimultaneously into the pleural space causing a bronchopleural fistula.Source: Canadian Tuberculosis Standards, 6 th Edition. Public Health Agency of Canada, 2007. Reproduced with the permission of theMinister of Public Works and Government Services, 2009. Available at www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdfLimitations of chest radiographySensitivity: chest radiography will have a sensitivity of only 70% to 80% for diagnosis of activeTB based on the abnormalities listed above. If any abnormality is considered it will have morethan 95% sensitivity. Approximately 10% of HIV-positive persons or close contacts with activepulmonary disease will have normal X-raysSpecificity is relatively poor, in the range of 60% to 70%. If the sensitivity were improved (anyabnormality considered possible TB), then the specificity would be much lowerInter reader variability: one of the greatest problems with chest X-ray reading is that theinterpretation is highly variable. There is very poor agreement between readers regarding thepresence of cavitation, hilar lymphadenopathy and the likelihood of active disease. 30Source: Canadian Tuberculosis Standards, 6 th Edition. Public Health Agency of Canada, 2007. Reproduced with the permission of theMinister of Public Works and Government Services, 2009. Available at www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdfRecommendation:Chest X-ray is not considered the gold standard for the diagnosis of pulmonary TB.Chest X-ray in pregnancyThe decision to perform a chest X-ray on women undergoing evaluation for active TB disease duringpregnancy should be made on a case-by-case basis following discussion between the respiratory physician/infectious disease consultant and the consultant radiologist. A lead shield should be used if a chest X-ray isperformed. 77Chest X-ray in childrenChest X-ray is useful in the diagnosis of TB in children. Children should have an anterior-posterior chestX-ray which should be read by a radiologist experienced in paediatric radiology. A lateral chest X-ray istaken only in certain cases and generally after consultation with a radiologist. In the majority of cases,children with pulmonary TB have chest X-ray changes suggestive of TB. The most common finding ispersistent opacification in the lung in conjunction with enlarged hilar or subcarinal lymph glands. A miliarypattern of opacification in HIV-uninfected children is highly suggestive of TB. Patients with persistent-24-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCopacification which does not improve after a course of antibiotics should be investigated for TB. More thanhalf of children with radiological pulmonary disease are asymptomatic (identified through contact tracing).The chest X-ray is typically “sicker” than the child. 77-25-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC3. Management of Latent TB InfectionAn estimated one-third of the world’s population is infected with M. tuberculosis. Some of these infectionsare latent TB infections (LTBI) i.e. when the bacteria remain inactive in the body, although they can bereactivated later. People with LTBI have no symptoms and are not infectious but they usually have apositive TST or IGRA and may develop active TB disease if not treated. Approximately 10-15% of thosepresumed infected may eventually develop the active disease at some point in their lives. Approximately50% of those persons who develop clinical disease do so within five years of the initial infection, with theremaining 50% reactivating over ensuing years. 26If co-morbidity develops impairing the immune system e.g. HIV infection, this risk further increases. In caseswhere there is a long period documented between the exposure and the development of disease, dormantbacilli are thought to remain in either the lung or other sites, which can be ‘reactivated’ if favourablecircumstances for the organism occur. However not everyone with LTBI will develop active TB disease. Themajority of exposed persons will kill off the TB bacteria and will be left only with a positive skin test as amarker of exposure.LTBI should be treated to prevent the development of active TB disease with its associated risk of thespread of TB and the development of outbreaks. Treatment of people with LTBI, including those with HIVco-infection, effectively reduces the risk of progression to active TB disease. However, there is no accuratetool to predict which individuals with LTBI are at greatest risk of developing active disease.A person with LTBI usually has a positive TST or IGRA but no physical findings of TB disease and the chestX-ray is normal or only reveals evidence of healed infection i.e. granulomas or calcification in the lung, hilarlymph nodes or both. Persons with LTBI can develop TB disease later in life.The following table outlines the difference between LTBI and active TB disease (table 3.1).Table 3.1: Differences between LTBI and active TB diseaseA person with latent TB infectionNo symptomsUsually have a positive skin test or blood testSputum is TB smear and culture negativeNormal chest X-ray or evidence of healedinfectionNot infectiousA person with active TB diseaseHas symptoms which may include• Unexplained productive cough lasting 3weeks or more• Chest pain• Productive cough/haemoptysis• Weakness or fatigue• Weight loss• Anorexia• Chills• Fever• Night sweatsUsually have a positive skin test of blood testMay have a positive sputum smear/cultureMay have an abnormal chest X-rayMay be infectious3.1 Epidemiology of LTBIIn the USA, it is estimated that approximately 10 to 15 million persons have LTBI. Particularly high rates ofinfection are found among the urban poor such as intravenous drug users and homeless persons. 78;79 Theelderly also have high rates of positive TST tests attributable to the much higher risk of TB infection during-26-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCtheir youth. Among the foreign-born, prevalence of infection is correlated with incidence of TB in theircountry of origin and the age of immigration.The contacts of active TB cases also have a high prevalence of TB infection with the risk of infection beinghigher if the index case is pulmonary sputum smear positive or if the contact is close. However, absolutelevels of risk have been estimated in relatively few of the studies that measured the prevalence of infectionin non-contacts in the general population. 36In 2005, a study was undertaken in a large Dublin teaching hospital which reviewed the screening data fortwo groups of persons, namely new employees (n= 2,410) and a high-risk group of HIV positive patientsattending the hospital (n= 331). 80 Cases with positive TSTs were offered chest X-rays and if clear of TB werecategorised as LTBI. The study found that 31.7% of the HCWs had LTBI while 11% of the HIV positive grouphad LTBI.There is little information in relation to the prevalence of LTBI in Ireland.Diagnosis of LTBIThere is no gold standard test for LTBI and therefore diagnosis of active or latent TB involves a numberof tests. In asymptomatic persons, exposure to and potential infection with TB can be demonstrated bya positive TST or a positive IGRA. In practice, the TST is the standard method of determining whethera person is infected with M. tuberculosis. Reliable administration and reading of the TST requiresstandardisation of procedures, training, supervision and practice. Individuals with positive skin tests areregarded as having been infected with TB. Neither TST nor IGRA can distinguish active TB disease fromLTBI. Further details on the diagnosis of LTBI i.e. TSTs, IGRA and chest X-rays are outlined in chapter 2.3.2 Risk Factors for LTBITB may be transmitted from a person with active TB disease and is much more likely to be transmittedfrom an active respiratory TB case. However, some individuals are more likely than others to develop TBinfection when exposed. The most important risk factors for developing TB infection are the extent of theexposure and the infectivity of the source case. 52 Risk factors for developing TB infection are outlined asfollows:• Closeness of contact with a source case: close contacts at greatest risk• Duration of exposure to a source case: brief exposure carries low risk• Sputum status of source case: sputum smear positive case carries greatest risk• Extent of pulmonary disease of source case: cavitation and cough carry greatest risk• Laryngeal TB: carries the highest transmission risk• Age: prevalence increases with age but incidence is highest in young children. In young children,the risk of disease after infection is up to 40% 81• Cough frequency of source case: higher cough frequency results in higher risk. However,cough frequency is a less statistically significant indicator of infectivity than extent of disease orbacteriological status• Delay in diagnosis or appropriate treatment of source case: effective chemotherapy of thesource case progressively reduces infectiousness (and therefore risk to contacts)• Open skin TB abscess: dressing or irrigation of an open abscess can lead to infection• Residence in institutions.BRisk factors for LTBI progressing to active TB diseaseThe risk of an individual with latent TB developing active TB varies depending on a number of factors(tables 3.2 and 3.3). 52-27-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 3.2: Risk factors for developing active TB disease following LTBIRisk factorTime since infectionAgeDose of infectionSize of tuberculin reactionPredisposing medicalconditionsImmunosuppressivetreatmentImmigrants who haverecently arrived from a highincidence countryBody weightCommentRisk is highest in the first two years after infectionInverse association: Peaks in increased risk occur in the preschool yearsand adolescence/early childhoodRisk higher if the source case is smear positive; less if smear negative/culture positive; minimal if culture negativeThe larger the reaction the greater the risk of subsequent disease.However, there is a substantial degree of variation in the extent ofincreased risk associated with larger tuberculin reactions (table 2.1,chapter 2) 82HIV is the strongest risk factor. Other risk factors include: chronic renalfailure or receiving haemodialysis, diabetes, haematological malignancy,jejeunoileal bypass or gastrectomy, silicosis, alcoholism and drugaddiction including injecting drug users and solid organ transplantationCurrent or recent oral steroids, some cancer therapy, immunosuppressivedrugs, receiving Tumour Necrosis Factor-α (TNF-α) antagonist treatmentRisk is highest in the first two years 83;84There is an increased risk associated with being underweight ormalnourishedReproduced with kind permission from <strong>Guidelines</strong> for tuberculosis control in New Zealand. New Zealand Ministry of Health (2003).Available at www.moh.govt.nz/moh.nsf/pagesmh/2046?Open-28-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 3.3 Risk factors for the development of active TB among persons infected with M. tuberculosis 30High RiskRisk FactorEstimated risk of TB relative topersons with no known risk factorAIDS 110-170 85HIV infection 50-110 6Transplantation (related to immunosuppressant therapy) 20-74 86Silicosis 30 87Chronic renal failure requiring haemodialysis 10-25 88Carcinoma of head and neck 16 89Recent TB infection (≤2 years) 15 90Abnormal chest X-ray – fibronodular disease 6-19 91Increased riskTreatment with glucocorticoids 4.9 92Tumour necrosis factor (TNF)- alpha inhibitors 1.5-4.0 93Diabetes mellitus (all types) 2.0-3.6 94Underweight (

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCIt is recommended that all age groups in priority groups 1 to 5 listed below should be considered fortreatment of LTBI. This is similar to the US strategy for treatment of LTBI which recommends no age limitsas the risk of severe fatal hepatoxicity from treatment with anti-TB drugs is considered low even in thoseaged over 35 years and if testing and treatment are targeted at these high risk groups then the risk: benefitratio should be acceptable. 100 Recommendations for LTBI treatment in priority groups 6 to 9 are also listedbelow.The following groups should be prioritised for the treatment of LTBI [see table 2.1 for TST (Mantoux) cutoff points for treatment of LTBI in these groups]:1. Recent converters2. HIV positive individuals3. Those aged less than five years4. Persons receiving immunosuppressive therapy i.e. Tumour Necrosis Factor-α (TNF-α) antagonists5. Persons with evidence of old healed TB lesions on chest X-ray i.e. fibronodular disease/noncalcifiedfibrotic lesions (if not previously treated or if treated, not adequately treated) 30;776. Foreign-born persons from countries with high TB endemicity1#7. Homeless persons8. Intravenous drug users9. HCWs.The risk of isoniazid toxicity has been shown to increase with age in particular in persons aged 55 years andolder. 77Recommendation:Groups 1-5: LTBI treatment should be offered to those in all age groupsGroups 6-8: LTBI treatment should be offered to all those aged ≤ 55 years if supervisedtreatment (DOT) † † is available. Otherwise it should be offered to those aged ≤35 years. Thesegroups should be closely monitored for isoniazid toxicity 77Group 9: The age limit for LTBI treatment should be assessed on a case-by-case basis i.e.treat all HCWs where the risk of progression from LTBI to TB disease is high regardless of age.Where the risk of progression is low, the upper age limit is ≤35 years (chapter 9)All others not mentioned above: The upper age limit should be ≤35 yearsCare should be taken when prescribing LTBI therapy for those with co-morbidities whichincrease the likelihood of hepatotoxicity.Management of Persons Exposed to Infectious TB after Previous LTBI TreatmentVery high risk severely immunocompromised persons (e.g. those with HIV infection) who are re-exposedto TB infection, having already completed a satisfactory course of LTBI therapy should be considered for arepeat course of treatment for LTBI. If questions arise regarding risk of TB following repeat LTBI, referral toa respiratory physician or an infectious disease consultant is recommended. 30# Countries where the annual rate of TB disease is ≥40 cases/100,000 population† † A way of helping patients to take their medicine for TB. A person receiving DOT will meet with a healthcare worker everyday orseveral times a week at an agreed place e.g. the patient’s home, the TB clinic or other convenient location. The healthcare workerwill observe the patient taking their medication at this place helping to ensure that higher treatment completion rates are achieved.Sometimes someone in their family or a close friend will be able to help in a similar way to the healthcare worker. Further definitionsare available in the glossary of terms.-30-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC3.4 Treatment of LTBIThe choice of treatment regimen for LTBI will depend on:• The presence or absence of risk factors for progression to TB disease• An assessment of the likely adherence level of the patient and the amount of time available forcompletion of the patient’s treatment• The antibiotic susceptibility of the presumed source case• Drug tolerance of the patient.Poor adherence is the most important reason for the failure of LTBI treatment. Many people with LTBI donot complete treatment as most are not sick and may not feel the urgency to complete the prolongedtherapy. Directly observed therapy (DOT) for LTBI is an excellent method for promoting adherence totreatment. 77 Because of limited resources, DOT (supervised therapy) for LTBI cannot be offered to allpersons on LTBI treatment, however, it should be provided to those in the priority groups 6, 7 and 8mentioned above.However, for all others receiving LTBI treatment, a great deal can be accomplished to improve adherenceby developing a relationship based on trust and support between the healthcare worker and patient. 30Barriers to adherence should be addressed and overcome (appendix 4) 77Recommendation:Directly observed therapy (DOT) should be provided for those being treated for LTBI in groups6, 7 and 8 above i.e. immigrants from areas of high TB endemnicity, homeless persons andintravenous drug users.Recommendation:It is recommended that audits of compliance with LTBI therapy are undertaken.Treatment of LTBI in adultsThe effectiveness of isoniazid in preventing progression from LTBI to active TB disease was first reported in1957 and has been confirmed by many studies since. Isoniazid is the most widely used anti-TB agent as it isrelatively non-toxic, easily administered and inexpensive.Similar treatment regimens for LTBI in adults are recommended by the UK 26 and New Zealand. 52The NICE guidelines 26 recommend that non HIV-infected adults are treated with either (i) six months ofisoniazid or (ii) three months of rifampicin and isoniazid or six months of rifampicin for contacts of isoniazidresistant TB cases. This recommendation applies to persons aged 16-35 years and to persons older than35 years for whom treatment of LTBI is recommended. These recommendations are based on a Cochranereview of randomised trials of isoniazid of at least six months duration which were placebo controlled withat least two years follow up. 101 This review states that the efficacy of treatment increased with the durationof treatment but that the efficacy of six months or 12 months did not vary significantly. In fact, the smalladvantage of 12 months over six months may not be worthwhile except in those individuals at high risk ofdeveloping TB.The American Thoracic Society (ATS) 2000 34 , Canadian (2007) 30 and New York guidance (2008) 77recommend similar treatment regimes of daily isoniazid for nine months. Alternatively, a regime ofrifampicin for four months may be used if isoniazid is contraindicated due to a history of an isoniazid--31-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCinduced reaction or for a contact of an isoniazid resistant-TB case or if the patient may not be able toadhere to therapy for a six to nine month period.ATS guidelines state that although nine months of isoniazid was the preferred regimen for the treatmentof LTBI, a six month regimen also provides substantial protection and has been shown to be superior toplacebo in both HIV negative and HIV positive persons. However, treatment for six months rather than ninemonths may provide more favourable outcomes from a cost effectiveness standpoint. 34The rationale for the ATS recommendations was based on evidence from randomised controlled clinicaltrials that assessed the benefits of isoniazid. These studies showed that isoniazid was effective inpreventing TB disease. Most of the studies compared isoniazid for 12 months with placebo. However, onetrial, conducted by the International Union Against Tuberculosis and Lung Disease (IUATLD), was designedto evaluate various durations of isoniazid and this indicated that a 12 month regimen provided a substantialreduction in risk compared with a six month regimen among compliant persons with small lesions. 102 Afurther reanalysis of data from community studies in Alaska indicated that the protection conferred bytaking at least nine months of isoniazid was considered greater than taking six months but it was not likelythat further protection was conferred by extending the duration of treatment from nine to 12 months. 103Based on a review of the evidence and guidance in the international literature and by consensus of theNational TB Advisory Committee, the following are the recommended treatment regimens for LTBI inadults:Recommendation:The recommended treatment regimens for LTBI in adults are:(i) Isoniazid for a minimum of six months with an optimum duration of nine monthsor(ii) Rifampicin for four monthsor(iii) A combination of rifampicin and isoniazid for a duration of at least three months with anoptimum of four months.Treatment of LTBI in childrenThe US Centers for Disease Prevention and Control (CDC) defines paediatric TB as occurring in personsaged less than 15 years. 104 LTBI in a child can be defined as a child or adolescent with a positive TST whohas no evidence of TB disease.Infants and young children under the age of five years with LTBI have been only recently infected andtherefore are at a higher risk of progressing to active TB disease. The literature suggests that 40% ofuntreated infants will develop active TB disease although the risk of progression decreases throughoutchildhood. 105 These children are also more likely than older children and adults to develop life-threateningforms of TB disease in particular meningeal and disseminated disease. Among children the efficacy oftreatment of LTBI with isoniazid approaches 100% with appropriate adherence to therapy. Hepatotoxicityfrom isoniazid in infants and children is rare and in general children tolerate the drug better than adults. 106International recommendations for treatment of LTBI in childrenThe American Academy of Pediatrics and CDC convened the Pediatric Tuberculosis Collaborative Group.This group produced a consensus document which stated that treatment is recommended for all childrenand adolescents diagnosed with LTBI because: 105• The drugs used are safe in the paediatric population• Infection with M. tuberculosis is more likely to have been recent-32-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• Young children are at a higher risk of progression to TB disease and• The paediatric population has more years to potentially develop TB disease.The Pediatric Tuberculosis Collaborative Group also recommended:• TB disease should be excluded by chest X-ray and examination before initiating treatment for LTBI• That the regimen for treatment of LTBI in children and adolescents should be isoniazid either dailyor twice weekly for nine months and• That if the source case is isoniazid resistant, rifampicin should be used daily for six months.The collaborative group recommendations were based on clinical trials, which showed that treatmentof LTBI in children with isoniazid therapy reduces the risk of progression to active disease. 34 The onlypublished efficacy trials of treatment of LTBI in children are for isoniazid alone with a recommendedregimen for treatment of LTBI in HIV non-infected children of a nine month course of isoniazid daily ortwice weekly by DOT.Based on a review of the evidence and guidance in the international literature and by consensus of theNational TB Advisory Committee, the following are recommended treatment regimens for LTBI in children:Recommendation:The recommended treatment regimens for LTBI in children are:(i) Isoniazid for a minimum of six months with an optimum duration of nine monthsor(ii) Rifampicin for six monthsor(iii) A combination of rifampicin and isoniazid for a duration of four months.Physicians experienced in the management of children with LTBI should supervise treatment.3.5 Treatment of Multidrug-Resistant or XDR LTBIA source case can be sputum smear positive for MDR-TB or XDR-TB and therefore contacts have to bemanaged in the appropriate manner. The WHO recommends that close contacts of MDR-TB or XDR-TB patients should receive careful clinical follow-up for a period of at least two years. If active diseasedevelops, prompt initiation of treatment with a regimen designed to treat MDR-TB or XDR-TB isrecommended. On the basis of currently available evidence, WHO does not recommend the universal useof second-line drugs for chemoprophylaxis in MDR-TB or XDR-TB contacts. 107 It is also recommended thatthe management and follow-up of contacts aged

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC3.6 Pre-treatment EvaluationThe pre-treatment evaluation (figure 3.1) of persons who are targeted for treatment of LTBI provides anopportunity for healthcare providers to:• Establish a rapport with the patient• Discuss details of the patient’s risk of TB• Emphasise the benefits of treatment and the importance of adherence to the drug regimen• Review possible adverse effects of the regimen, including interactions with other drugs, and• Establish an optimal follow up plan.The evaluation should include an interview conducted in the patient’s primary language with the assistanceof qualified medical interpreters, if necessary.The patient history should document:• Risk factors for TB• Prior treatment for TB or LTBI• Pre-existing medical conditions that may be contraindications to treatment or are associated withan increased risk for adverse effects from treatment and• Current and previous drug therapy, with particular attention to previous adverse reactions to drugsand to current drugs which may interact with LTBI treatment e.g.o Isoniazid: interacts with antacids (decrease absorption of isoniazid)o Phenytoin and carbamezapine (isoniazid decreases metabolism of these drugs henceleading to increased blood levels); and corticosteroids (concentration of isoniazid possiblyreduced by corticosteroids)o Rifampicin: causes reduced levels of many drugs including warfarin, methadone, oralcontraceptive pill, oral hypoglycaemic agents, theophylline, ketoconazole, dapsone, PIsand NNRTIs) (figure 3.1). 77Recommendation:Clinicians may choose to undertake baseline liver function tests (LFTs) for all patients agedover 14 years at the start of treatment for LTBI. However, this is not universally obligatory.However, baseline LFTs should be done on the following persons prior to commencing therapy for LTBI:1. Everyone over the age of 35 years2. All HIV-infected persons3. Pregnant or post-partum women (up to 2-3 months postpartum)4. Those with a history of hepatitis, liver disease or heavy alcohol ingestion5. Injecting drug users6. Those on treatment with other potential hepatotoxic agents.All patients prescribed a rifampicin-containing regime should have a baseline full blood count andplatelets. 52;77Patients with baseline transaminases of more than three times the upper limit of normal (ULN) ‡ ‡ 2should have the ALT and bilirubin retested. Screening for viral or other causes of hepatitis including alcoholand hepatotoxic drugs should also be undertaken. In this situation, the decision to treat LTBI or more likelyto defer treatment should be carefully made on a case-by-case basis weighing the risk of progression to TBdisease against the risk of isoniazid or rifampicin drug induced liver injury (DILI). Factors influencing the risk2 ‡ ‡ The upper limit of normal (ULN) used should be that of the laboratory performing the assay.-34-

B<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCof DILI include the degree of baseline ALT elevation, alcohol consumption, increasing age and evidence ofactive replication of the hepatitis virus.If LTBI treatment is started, some experts recommend measuring the serum transaminases and bilirubinconcentrations every 2 to 4 weeks for the first 2 to 3 months of treatment. The international normalisedstandard (INR) may be followed periodically as well in patients with severe hepatic impairment. 108Figure 3.1: Latent tuberculosis infection (LTBI) pretreatment clinical evaluation and counselling*Potential eligible patient for LTBItreatment based on risk factorsRe-evaluateHepatology evaluationYesDefer treatmentIdentify risk factors for hepatotoxicity, ask if :Chronic alcohol consumptionViral hepatitisPre-existing liver disease2-3 months post-partumConcomitant hepatotoxic medicationsPrevious ALT/AST or LFTs abnormalHIV infectedAge >35YesCheck baselineALT/AST andbilirubinYesALT/AST or LFTs >= 3 xULN if symptomatic, >=5x ULN if asymptomaticDefer LTBItreatment until 2-3months postpartumNoLow riskAssess TB risk(Treat pregnant patientwho is HIV-positive, closecontact or documentednew converter)YesPregnantNoHigh riskCheck ALT/AST and LFTsprior to beginning treatmentand follow closelyNoRegimen selection according to indication and risk of drug-induced liver injury:Isoniazid x 6 months, 9 months optimalRifampicin x 4 months (6 months in children) e.g. if ALT 2-3 x ULN, isoniazidresistanceor hepatotoxicity, need to complete treatment in short timeCombination of rifampicin and isoniazid x 3 months, 4 months optimal (4 monthsin children)Patient educationUse patient’s preferred languageReview hepatitis symptoms and signsDiscontinue treatment at symptom onset and contactclinicDocument patient education in chartMonitoring plan inmedical recordALT = alanine aminotransferase; AST = aspartate aminotransferase; LFTs = liver function tests; ULN = upper limit of normal* Adapted from the New York City Department of Health and Mental Hygiene TB guidelines-35-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC3.7 Drug Regimens for LTBIIsoniazid is used alone for preventive therapy for a minimum of six months with an optimum duration ofnine months. The drug is given in a single daily dose of 5mg/kg (max dose: 300mg) per day for adults and5-10mg/kg (max dose: 300mg daily) for children. 77 Ideally, anti-TB therapy for the treatment of LTBI shouldbe dispensed in monthly allocations. However in some situations, if the clinician or public health doctordeems it appropriate it may be dispensed at less frequent intervals e.g. every two months. If isoniazidcannot be given daily, it can be given twice weekly in a dose of 15mg/kg (up to 900mg) for adults and 20-30mg/kg (up to 900mg) for children (see table 3.4). 77;109For persons intolerant to isoniazid or who are likely to be infected with isoniazid resistant organisms,rifampicin for four months may be used (see table 3.4).Dosages for drugs commonly used for treatment of LTBI are outlined in table 3.4. For treatment with otherdrugs, referral to a clinician experienced in TB is advised, particularly for contacts of MDR-TB cases (section3.5).Table 3.4: Drug Regimens for LTBIDrug anddurationDailyDosageTwice weeklyMajor adverse reactionsRecommendedmonthly monitoring 1CommentsIsoniazidChildren:6 monthsoptimumAdults:9 monthsoptimumChildren:5-10mg/kg(max 300mg)Adults:5mg/kg(max 300mg)CompletionCriteria:270 doseswithin 12monthsChildren:20-30mg/kg(max 900mg)Adults:15mg/kg(max 900mg)CompletionCriteria:76 doseswithin 12 monthsSymptoms: Unexplainedanorexia, nausea, vomiting,dark urine, jaundice, persistentfatigue, weakness, abdominaltenderness (especially rightupper quadrant discomfort),easy bruising or bleeding, rash,persistent paresthesias of thehands and feet, arthalgiaSigns: Elevated LFTs, hepatitis,icterus, rash, peripheralneuropathy, increased phenytoinlevels and possible interactionwith disulfiramClinical evaluation: LFTs (ifbaseline is abnormal or patienthas risk factors for toxicity) 2Preferred regimenfor all individualsVitamin B6 (25mg/day)or pyridoxine maydecrease peripheraland CNS effects, andshould be used inpatients who are:- Abusing alcohol- Pregnant- Breastfeeding infantson isoniazid- MalnourishedOr who have- HIV- Cancer- Chronic renal or liverdisease- Diabetes- Pre-existingperipheralneuropathyNote: aluminiumcontainingantacidsreduce absorption-36-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 3.4 contd.Drug anddurationDailyDosageTwice weeklyMajor adverse reactionsRecommendedmonthly monitoring 1CommentsRifampicinChildren:6 monthsAdults:4 monthsChildren:10-20mg/kg(max 600mg)Completioncriteria:182 doseswithin 9 monthsAdults:600 mg(range: 8-12mg/kg)(max: 600mg)Completioncriteria:120 doseswithin 6 monthsChildren:not recommendedAdults: 3600mg(range 8-12 mg/kg)(max 600mg)Completion criteria:34 doses within 6monthsSymptoms: Nausea, vomiting, rash,fever or flu-like symptoms, easybruising.Signs: Elevated LFTs, hepatitis,rash, thrombocytopeniaReduced levels of many drugsincluding methadone, warfarin,hormonal contraception,oral hypoglycaemic agents,theophylline, dapsone,ketoconazole, PIs and NNRTIsClinical evaluation:- LFTs (if baseline is abnormal orpatient has risk factors for toxicity) 2- Complete blood count, includingplatelets as neededMay be used totreat personswho have beenexposed toisoniazid-resistant,rifampicinsusceptibleTB,or who havesevere toxicity toisoniazid, or whoare unlikely to beavailable for morethan 4-6 months.Be aware that- There willbe orangediscoloration ofsecretions, urine,tears and contactlenses- Patients receivingmethadonewill need theirmethadonedosage increasedby an average50% to avoidopioid withdrawal- Interactions withmany drugs canlead to decreasedlevels of either orboth- Rifampicin maymake glucosecontrol moredifficult indiabetics- Rifampicin iscontraindicatedfor patients takingmost PIs andNNRTIs- Patients shouldbe advisedto use barriercontraceptiveswhile onrifampicin1Baseline LFTs should be done for everyone over the age of 35, all HIV-infected persons, pregnant and post-partum women (up to2-3 months post-partum), those with history of hepatitis, liver disease or alcohol abuse, injection drugs users and those on treatmentwith other potential hepatotoxic agents. A baseline CBC with platelets should be done on anyone prescribed a rifampicin-containingregimen2Monthly LFTs should be conducted for all HIV infected persons, pregnant and post-partum women (up to 2-3 months post-partum),those with history of hepatitis, liver disease or alcohol abuse, injection drugs users and those on treatment with other potentialhepatotoxic agents. Those whose baseline LFTs were abnormal should be monitored monthly regardless of other conditions.3There is very little data or clinical experience on the use of intermittent treatment of LTBI with rifampicin. This regimen should beused with caution.Reproduced with kind permission from Tuberculosis, Clinical Policies and Protocols. New York City Department of Health and MentalHygiene (2008). Available from www.nyc.gov/html/doh/downloads/pdf/tb/tb-protocol.pdf.-37-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCPyridoxineIt is believed that isoniazid competes with pyridoxyl phosphate for the enzyme apotryptophanase, whichmay lead to symptoms of pyridoxine (vitamin B6) deficiency. Pyridoxine administration may decrease theperipheral and CNS effects complicating isoniazid use. If on isoniazid, pyridoxine 10mg daily (20mg dailymay be used if 10mg tablets are not available) should be prescribed for:• all adults, including pregnant women• children who have poor nutrition and therefore are at risk of pyridoxine deficiency• children who develop paraesthesia• breastfeeding infants on isoniazid• a fully breastfed infant if the mother is on isoniazid, regardless of whether the infant is on anti-TBtreatment• In particular, those with, pre-existing peripheral neuropathy, diabetes, chronic renal or liver disease,52 77cancer, alcoholism, malnutrition, other immunosuppressive conditions or HIV.As there are no side effects to low dose pyridoxine, many centres routinely prescribe it to prevent thedevelopment of neuropathy. 30 However, it is not routinely prescribed in children except in the situationsmentioned above.LTBI treatment: contraindicationsIsoniazid• Previous history of an isoniazid-induced reaction including hepatic, skin or allergic reaction• Close contact with a person who has isoniazid-resistant TB• Pregnancy: unless the woman is HIV infected or has been recently infected i.e. is a close contactof an infectious TB case. In these cases, a risk assessment should be undertaken on a case-bycasebasis and treatment deferred if possible until after the first trimester. Apart from the abovesituations, the small benefits of LTBI treatment in pregnancy are not thought to outweigh the smallrisks associated with taking the medicationso For all other pregnant women, treatment if indicated for LTBI (provided active TB disease isexcluded) should be deferred until two to three months post-partum (figure 3.1)o The need to treat active TB disease during pregnancy is unquestioned. Treatment of LTBIis more controversial since the possible risk of hepatotoxicity must be weighed against therisk of developing TB diseaseo In pregnant women known or suspected to be infected with a TB strain resistant to at leastisoniazid and rifampicin treatment for LTBI should be deferred until after delivery. This willavoid possible adverse effects of the medications on the developing foetus. 30;34;77An alternative regimen to isoniazid is to give patients (with or without HIV infection) four months ofrifampicin for treatment of LTBI. This course is especially recommended if there are contraindications orresistance to isoniazid but not to rifampicin and if there may be adherence problems and the individual isunlikely to complete a six or nine month course of therapy.Rifampicin• A history or rifampicin-induced reactions including skin and other allergic reactions, hepatitis orthrombocytopenia• Pregnancy unless the woman is HIV infected, has been recently infected and is a close contactof an isoniazid-resistant case or is intolerant to isoniazid (see under isoniazid and figure 3.1)• Current treatment with a protease inhibitor (PI) or certain non-nucleoside reverse transcriptaseinhibitors (NNRTIs). 77-38-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCLTBI treatment: precautionsPersons with any of the conditions outlined below should be referred to a respiratory clinician or infectiousdisease consultant for treatment of LTBI:• Acute or chronic liver disease of any aetiology• Acute liver disease: If a person with acute liver disease has a high risk of progression to TB diseasefor example if the person is on immunosuppressive therapy and also had prolonged contact with ahighly infectious TB case, then a risk assessment should be carried out to determine whether theyshould be treated for LTBI• Receiving other drugs which may interact with anti-TB drugs• History of heavy alcohol ingestion• History of previous discontinuation of isoniazid because of possible, but not definite, related sideeffects e.g. headaches, dizziness, nausea• Major concerns about adherence to treatment• Major concerns about adherence to arrangements for biochemical or clinical monitoring• Peripheral neuropathy or risk factors for its development e.g. insulin dependent or type II diabetes,alcoholism, chronic renal failure or malnutrition. Pyridoxine 10mg daily (or 20mg if 10mg notavailable) should be offered to these patients (see section on pyridoxine).Recommendation:A consultant with expertise in TB should always be consulted when treating a patient with LTBIwith documented hepatotoxicity.A risk-benefit approach on a case-by-case basis should be adapted to commencing treatment for LTBI onthese patients. Treatment of patients with underlying liver disease should be undertaken in consultationwith a consultant hepatologist.Recommendation:Breastfeeding is not a contraindication to LTBI therapy. Isoniazid or rifampicin are not secretedin sufficient quantities in breast milk to harm the baby. 52;77Monitoring during treatmentClinical monitoring is indicated for all patients and ideally involves monthly visits, or at the discretion ofthe physician, where patients are educated about the symptoms and signs that can result due to adverseeffects of the drug(s) being prescribed and the need for prompt cessation of treatment and clinicalevaluation should symptoms occur.The symptoms of adverse affects include: 34;52• unexplained anorexia• nausea• vomiting• dark urine• jaundice• rash• persistent paresthesia of the hands and feet• persistent fatigue-39-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• weakness or fever lasting three or more days• abdominal tenderness (especially right upper quadrant discomfort)• easy bruising or bleeding and• arthralgia.The interval between commencing isoniazid and the appearance of hepatitis varies widely. Using astandardised proforma may facilitate monthly clinical monitoring (appendix 5). Appropriate educationalmaterials (information leaflet) in the patient’s language should be provided (appendix 6).Liver function tests (LFTs)Monthly LFTs during treatment of LTBI are indicated for patients whose baseline liver function tests areabnormal and for all HIV-infected persons, pregnant and post-partum women (up to 2-3 months postpartum),those with a history of hepatitis, liver disease or heavy alcohol ingestion, injecting drug users andthose on treatment with other potential hepatotoxic agents. 77Some experts recommend that healthy adults aged >35 years on LTBI treatment with isoniazid or isoniazidwith rifampicin have eight weekly monitoring of LFTs or at one, three and six months for those on a ninemonth regimen. The frequency depends on the perceived hepatotoxicity risk and effectiveness of patienteducation. 108In addition, laboratory testing (e.g. liver function studies for patients with symptoms compatible withhepatotoxicity or a uric acid measurement to evaluate patients who develop acute arthritis) should be usedto evaluate possible adverse effects that occur during the course of treatment.Interventions for hepatotoxicity during treatment for LTBIIf hepatic side-effects occur during treatment, expert advice should be sought from the treating physician.A hepatology evaluation should be undertaken and hepatology consultation is recommended for unusualor severe cases of hepatitis particularly those who become sufficiently ill to require hospitalisation. 108Isoniazid should be withheld if hepatic transaminases (ALT) are at least three times the ULN when thepatient is symptomatic (jaundice or symptoms of hepatitis) or if at least five times the ULN when the patientis asymptomatic. An isoniazid rechallenge should be considered when the ALT is less than twice the ULN.This should be decided by the treating physician on a case-by-case basis.A rapid increase in ALT may be an indication for more frequent monitoring i.e. every two weeks instead ofmonthly, particularly if one of the above treatment-limiting ALT thresholds is being approached or if thepatient has previously identified risk factors for hepatotoxicity.For the few patients who may begin isoniazid LTBI treatment with a baseline ALT >3 times the ULN, someexperts recommend that in the absence of adequate clinical data that treatment should be discontinuedif there is more than a two- to threefold increase above baseline or if there is a mental status change,jaundice or significant increase in bilirubin or INR. 108More detailed information on the hepatoxicity of anti-TB therapy is available in the Official AmericanThoracic Society’s Statement: Hepatotoxicity of Anti-TB Therapy. 108Recommendation:Ideally monthly clinical monitoring (at the discretion of the clinician) is recommended for allpatients receiving treatment for LTBI.-40-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCInterruptions in therapyAdherence to treatment regimens is recognised as a significant problem, especially in relation to thetreatment of LTBI, with CDC stating that only 60% of patients who start treatment for LTBI complete atleast six months of treatment. 34 The length and complexity of the regimen and the side effects of themedication influence adherence to treatment. Directly observed therapy (DOT) has been used to try toimprove adherence to treatment regimens. Ideally, patients should receive medication on a regular dosingschedule until completion of the indicated course. However, in practice some doses may be missed,requiring the course to be lengthened.If interruptions in therapy occur the person responsible for supervision must decide whether to restart acomplete course of treatment or whether simply to continue as originally intended.Completion of therapy is based on the total number of doses administered not on the duration of therapyalone. The nine month regimen of daily isoniazid should consist of a minimum of 270 doses administeredwithin 12 months, which allows for minor interruptions in therapy. The six month regimen of isoniazidshould consist of at least 180 doses administered within nine months. 34When therapy is restored after an interruption of more than two months, a medical examination to rule outactive TB disease is indicated.3.8 Risk of TB Associated with the Use of TNF-α AntagonistsTNF-α antagonists offer great promise to patients suffering a number of immune-mediated diseases andhave been used safely in many patients worldwide. However, it is plausible that these agents may carrya risk of reactivation of LTBI or of new TB infection. Concern is supported by the finding of a possibleincreased risk of TB in peer-reviewed publications from a number of countries. While the design ofthese studies does not allow causality to be concluded, the consistency of the studies and the temporalassociation with the agents, together with the gravity of the consequence for individual patients and forthe wider community suggest that a precautionary approach is appropriate. Manufacturers of TNF-αantagonists have indicated that TB is a possible side effect of treatment and a number of guidelines formanagement of this risk have been issued by professional organisations and individuals.The following recommendations (summarised in figure 3.2) are taken from a briefing paper preparedby members of the National TB Advisory Committee in consultation with members of the IrishSociety for Rheumatology. The full version of this document is available at: www.hpsc.ie/hpsc/A-Z/VaccinePreventable/TuberculosisTB/Guidance/.1. Prior to commencing TNF-α antagonists, patients should be thoroughly assessed for clinically activeTB disease, including clinical history, physical examination and chest radiograph. If clinically active TBdisease is diagnosed, it should be treated as per existing guidelines (chapter 5).2. Patients without clinically active TB disease should be screened for LTBI with clinical history, assessmentof risk factors (for example time spent living in a high incidence country, immunocompetence, etc.),physical examination, chest radiograph and TST.• IGRA testing may be a useful adjunct in screening where it is available.3. Patients without radiographic evidence of TB but with a positive TST should be classified as a case ofLTBI.• For the purpose of LTBI screening prior to commencing TNF-α antagonists, 2TU Mantoux testingis recommended. While reactions over 10mm should be interpreted as indicating TB infection,this cut off may not be reliable for some patients being considered for treatment with TNF-αantagonists since their disease and co-medications may lead to anergy. Therefore, the use of a5mm cut-off may be more useful for patients who are considered to be immunocompromised. It-41-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCis recognised that on the basis of individual risk assessment, clinicians may prefer to use an evenmore conservative cut-off for individual patients. Although a negative TST (Mantoux test) reducesthe probability of LTBI, a high clinical suspicion for LTBI should be maintained, since the reaction totuberculin may be complicated by anergy.• It is recommended that the interpretation of Mantoux testing in the context of testing for LTBIprior to commencement of a TNF-α antagonist should not usually take account of the patient’sBCG history.4. It is recommended that patients diagnosed with LTBI should be treated. Options for treatment includeat least nine months of isoniazid, which is associated with a lower risk of hepatotoxicity, or four monthsof rifampicin (R) +/- isoniazid, associated with a higher risk of hepatotoxicity but offers the advantageof shorter duration which may promote successful completion of treatment for some patients.Rifampicin for four months may also be used if isoniazid is contraindicated e.g. a past history of anisoniazid induced reaction. Pyridoxine may also be used in combination with these regimens.5. Optimal timing of initiation of TNF-α antagonists is challenging and in the absence of high-qualityevidence to support specific recommendations in this regard, decisions on the treatment of individualpatients need to be made collaboratively by patients and clinicians following a careful assessment ofthe risks of TB disease and the benefits of TNF-α antagonist treatment and discussion of individualpreferences.• Initiation of TNF-α antagonists prior to commencement of treatment of clinically active TB diseaseor LTBI should be avoided• The risk associated with commencement or re-commencement of TNF-α antagonists in thesetting of clinically active TB disease requires particularly careful assessment; where possible,it is recommended that TNF-α antagonists be postponed until curative treatment has beensatisfactorily completed; in some cases, clinicians and patients may prefer to avoid TNF-αantagonists completely in this scenario• The risk associated with commencement or re-commencement of TNF-α antagonists in thesetting of LTBI also requires careful assessment; again, where possible, it is recommended thatTNF-α antagonists be postponed until LTBI treatment has been satisfactorily completed. However,clinicians and patients may, on balancing risks and benefits, prefer to initiate TNF-α antagonistsduring treatment for LTBI; while no specific duration of LTBI treatment prior to initiation of TNF-αantagonists can be recommended on the basis of currently available evidence, where possible, alonger duration of satisfactory LTBI treatment is suggested as good practice in managing the riskof initiation of TNF-α antagonists.6. Clinically active TB disease may still arise in patients treated with TNF-α antagonists despite a negativeinitial assessment or LTBI treatment. Therefore, it is recommended that a high index of clinical suspicionfor development of TB is exercised in the setting of any clinical deterioration while patients areundergoing TNF-α blockade.7. Cooperation between clinicians initiating TNF-α antagonists and clinicians with expertise in TB isrecommended in the assessment and management of patients.8. Clinicians are encouraged to report all adverse drug events associated with the use of TNF-αantagonists to the Irish Medicines Board (IMB).It is suggested that these national recommendations provide a framework for the drafting of guidelinesfor use by individual professional societies, units and clinicians on the use of TNF-α antagonists in clinicalguidance; it is recognised that such guidelines may have broader concerns than the management of therisk of TB (e.g. surveillance for other side effects) and may wish to include local good practice advice,however, guidelines should be made cognisant of these recommendations.-42-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendation:Prior to commencing TNF-α antagonists, patients should be thoroughly assessed by thetreating physician for clinically active TB disease and for LTBI.Figure 3.2: Algorithm for TB assessment prior to the use of TNF-α antagonistsCheck for clinically active TB diseaseInclude clinical history, physical exam and chestradiographPOSITIVECurative treatmentNEGATIVECheck for LTBI2 TU Mantoux (>5mm may be a more usefulcut-off if immunosupressed)POSITIVETreatmentAt least 9 monthsisoniazid or 4 monthsrifampicin +/- isoniazid.Pyridoxine may beadded.NEGATIVETreat with TNF-α antagonistsMaintain a high index of clinical suspicion fordevelopment of TBRisk assessmentConsider initiation of TNF-α antagonists afterTB treatment commenced, if possiblepostpone until LTBI treatment is complete-43-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC4. Laboratory Diagnosis of Tuberculosis4.1 Role and Goals of the Modern TB LaboratoryThe microbiology laboratory makes a key contribution to TB control in terms of diagnosis, infectionprevention and control and management of the disease. The detection and isolation of mycobacteria,identification of the mycobacterial species or complex isolated and the determination of susceptibilities ofthe organism to anti-mycobacterial drugs are key functions of a modern TB laboratory. 110 The gold standardfor diagnosing active disease is by microbiological identification of TB by culture. Molecular typing ofisolates contributes significantly to understanding the epidemiology of TB. Population based molecularepidemiology studies have been used to evaluate TB control efforts, providing insights into transmissiondynamics, enhancing contact tracing and aiding the detection of laboratory cross-contamination. 111 Therole and importance of skilled and experienced staff cannot be over emphasised. 112In 1993, WHO declared TB a global emergency in response to an increase in cases after nearly a century ofdecline. Targets for achieving improved control were developed which involved diagnosing a minimum of70% of individuals with sputum smear positive TB and curing at least 85%. In Ireland, important legislativechanges have occurred since the publication of the 1996 TB guidelines. 113 In 2003, the Infectious DiseasesRegulations 1981 were amended by the Infectious Disease (Amendment) (No. 3) Regulations 2003 (S.I.No. 707 of 2003), stating that a clinical director of a diagnostic laboratory shall have regard to the casedefinitions for notification of infectious diseases. 21 The DPH or designated medical officer should benotified of the identification of a TB case ideally within one working day.Recommendation:It is a mandatory requirement for clinical directors of diagnostic laboratories to notify cases ofactive TB disease to the medical officer of health (director of public health or designate).Culture is necessary to achieve the “gold standard” for the diagnosis of active tuberculosisdisease.Levels of serviceBefore offering mycobacteriology services, each laboratory should assess the capacity and capability of thelevel of services performed. Clinical laboratories offering a mycobacteriology service are divided into threemajor categories of service (table 4.1). This follows recommendations by CDC and the American ThoracicSociety (ATS) stating that laboratories interpreting acid fast stained smears should process at least 10-15specimens per week to maintain proficiency and those processing specimens for culture should handle aminimum of approximately 20 specimens per week. 114-117 The majority of laboratories in Ireland are Level 2.Table 4.1: Levels of service for diagnostic microbiology laboratoriesLaboratoryservice levelLevel 1Level 2Collection and transport of specimens; preparation and examination of smears for AFB.Procedures of level 1, plus procedures for the isolation of Mycobacterium species.Identification of M. tuberculosis complex may or may not be performed.Level 3All procedures in level 2, plus identification of all species of mycobacteria. The determinationof drug susceptibility for all Mycobacterium species and typing of M. tuberculosis complexshould be performed at level 3.-44-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendation:Microscopy and culture for TB should only be performed in those laboratories where there issufficient throughput to ensure proficiency.In 1993, Tenover, 118 Huebner 119 and subsequently CDC 120 and Styrt 121 recommended by way of “goals” (notmandates or regulations) that a TB laboratory should report within certain time frames as shown in table4.2.Table 4.2: TB laboratory service goalsGoalsReport results of acid fast stainsDetect growth of mycobacteria in liquid mediumIdentify M. tuberculosis complex by mycolic acid pattern,AccuProbe or Bactec NAP testTime frame*Within 24 hoursWithin 10 daysWithin 3 weeksDetermine and report susceptibilities of new M. tuberculosisisolates to primary drugsWithin 3-4 weeks*Within receipt of specimen in the laboratoryRecommendation:Laboratories should aim to meet the “goals” set down by CDC and others.The Irish Mycobacteria Reference Laboratory (IMRL)The IMRL was established in 2001 to provide a timely reference service in relation to the diagnosis andtreatment of TB (see appendix 7 for contact details). Advice is available from a consultant microbiologist, arespiratory physician with expertise in the treatment of TB and senior laboratory scientists. The Departmentof Health and Children has set out the core functions that the reference laboratory service will be requiredto perform once it is fully developed. The IMRL functions include:• Identification of mycobacterial isolates• Sensitivity testing of isolates to anti-mycobacterial drugs• Assistance with isolation of mycobacteria in difficult cases• Provision of advice to clinicians and laboratories• Provision of clinical advice on diagnosis, treatment and infection prevention and control• Provision of a molecular diagnostic service for rapid identification• Molecular typing of M. tuberculosis• Training of medical/technical staff• Research• Provision of epidemiological information as required, subject to agreement with the HPSC.Some of the above services are currently not available. As the IMRL is developed, all of the services outlinedabove will be provided.-45-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendation:All mycobacterial isolates should be referred to the Irish Mycobacteria Reference Laboratory(IMRL) for identification and susceptibility testing once its new facility is opened.Recommendation:All M. tuberculosis complex isolates should be referred with immediate effect to the IMRL formolecular typing where typing is now offered.Recommendation:The results of all M. tuberculosis complex isolates which have already had identification,susceptibility and molecular typing performed should be forwarded to the IMRL forincorporation into a national repository of M. tuberculosis complex isolates.4.2 SpecimensAll specimens should be collected and submitted in sterile, clean, plastic, leak-proof, disposable, widemouthed,appropriately labelled, laboratory approved containers, without any fixative. Generally, transportmedia or preservatives are not needed owing to the robust nature of mycobacteria. 122 Swabs are notoptimal for the recovery of AFB. 122 Ideally specimens should be procured before chemotherapy is initiated.Even a few days of therapy can obscure the diagnosis because of the failure to recover mycobacteria. 123Specimens should be transported to the laboratory as soon as possible and refrigerated until processed.The transportation of infectious substances is subject to international legislation, to which laboratories arerequired to comply (section 4.7).Rejection of unsuitable specimensThe best mycobacteriological laboratory practices are frustrated if a poor or unsuitable specimen is presentedfor examination. Processing of inappropriate clinical specimens for mycobacteria can be wasteful, may berejected and the clinician notified.Examples of inappropriate specimens are as follows:• Insufficient amount submitted• Specimens consisting of saliva• Dried swabs• Pooled sputa or urine• Broken sample containers• Interval too long between specimen collection and processing 124• Analysis of urine specimens for the diagnosis of pulmonary TB.Recommendation:Reasonable efforts should be made to obtain the best quality sample possible depending onsite of disease and to deliver it in a timely fashion to the analysing laboratory.-46-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCSputum specimensA direct relationship between mucopurulent sputum and positive results has been demonstrated. 125Therefore, patients should be instructed as to the proper method of sputum collection. Ideally a 5-10mlspecimen 122;126 collected early in the morning § § on three consecutive days (with a minimum of one earlymorning specimen) prior to the commencement of treatment, if possible, is required (or failing that, withinseven days of commencement of treatment). 123;126;127 Failure to isolate M. tuberculosis complex (MTC)from appropriately collected specimens from persons suspected of having a pulmonary diagnosis doesnot exclude a diagnosis of active TB. Depending on the clinical features and differential diagnosis, otherdiagnostic testing such as induced sputa, bronchoscopy lavage and biopsy should be considered beforemaking a presumptive diagnosis of culture negative TB. 128Bacteriological monitoringBacteriological monitoring after diagnosis may be required to assist with a decision to discontinueisolation. The period of time a patient on effective therapy takes to become non-infectious varies. Patientswho have unrecognised or inadequately treated drug-resistant TB may remain infectious for weeks ormonths. 129 Laboratories can be overwhelmed with specimens obtained for the purposes of demonstratingsmear conversion in smear positive patients. This can also contribute to an increase in false positive casesin the laboratory. It should be noted that beyond 12 weeks of treatment, 63% to 73% of patients withpersistently positive smear results have negative culture results. In the absence of MDR-TB and XDR-TB, the persistence of AFB in smears at the end of therapy is not necessarily a treatment failure. 130;131Laboratories should liaise with clinicians to develop a protocol for processing such specimens. Follow-upsputum specimens for smear and culture should be obtained monthly in patients with drug-susceptiblepulmonary disease. For patients with isoniazid- and rifampicin-susceptible TB there is no need to examinesputum monthly once culture conversion is documented (i.e. two negative cultures taken at least 2 to 4weeks apart). 77 It is recommended that identification and sensitivities are repeated in cases who are stillculture positive at ≥ two months. If the patient has isoniazid and/or rifampicin resistant TB, sputum culturesshould be examined monthly until the end of treatment. 77 Bacteriological monitoring i.e. culture at theend of treatment is strictly recommended in confirmed cases of TB to assess precisely that the patient hasbeen cured. Culture positive Mycobacterium tuberculosis complex (MTC) from each different site shouldundergo identification and sensitivity testing.Induced sputum and fibreoptic bronchoscopyHypertonic saline can be nebulised for induction of sputum. Bronchoscopy is the next best choice becausethis procedure provides additional material for study, washings, brushings and biopsy specimens. Inducedsputum has been shown to be as sensitive 132 or more sensitive 133;134 than bronchoscopy and is also cheaperto perform. Sputum induction in children has been shown to be safe and useful for microbiologicalconfirmation of TB in children and preferable to gastric lavage. 135 Where facilities permit it may bepreferable to gastric lavage. 135The bronchoscopy procedure may cause the patient to continue producing sputum for several days. Theuse of bronchoscopy in evaluating children with TB is not routine but it can provide useful information inselected cases. 136 (See section 8.1. Chapter 8 for contact tracing) (See section 6.5. Chapter 6 for infectionprevention and control). These samples should also be collected and examined. 110Gastric washingsGastric lavage may be necessary for those patients, particularly children, who cannot produce sputumeven with aerosol inhalation. Fasting early morning specimens are recommended to obtain sputumswallowed during sleep. 124 These specimens should be processed within four hours or neutralised withsodium carbonate or another buffered salt to a pH of 7.0. It has been suggested that for these reasonsgastric aspiration is best performed by experienced staff. 137 AFB smear testing is unreliable due to thehigh prevalence of atypical mycobacteria in gastric lavage. Culture should only be used for further clinicalmanagement.UrineUrine is an inappropriate specimen for the diagnosis of pulmonary TB. The diagnosis of renal TB,disseminated TB or TB in severely immunocompromised persons can be aided by the culture of 3 early______________________________________§ §Early morning sputum: sputum from the first productive cough in the day (after waking)-47-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCmorning mid-stream urines each with a volume of 40-50ml. Smears of urine are usually negative and may notbe cost effective 110 or they may give unreliable results due to the presence of environmental mycobacteria thatmay be found in the lower urethra. 127 However, if examination of urine is restricted to those patients who areseverely immunocompromised, suspected of having renal or disseminated TB, or when haematuria or sterilepyuria has been demonstrated, the value of performing smears may be improved.FaecesFaecal specimens are largely used in the detection of Mycobacterium avium complex (MAC) from theintestinal tract of patients with HIV/AIDS, in conjunction with specimens from other sites. Interpretation mayalso be difficult due to the presence of saprophytic AFB frequently present in faeces samples. 127Cerebrospinal fluidCerebrospinal fluid (CSF) should be examined for protein, glucose and white cell count and differential.Lymphocytosis together with a low glucose and high protein are typical of TB meningitis. The volume of CSFis critical and a minimum of 5ml 110 but up to 10ml is ideally required 126;138 provided it is medically safe to obtainthis volume. Studies should be undertaken prior to the administration of anti-tuberculous chemotherapy.There is a low yield of approximately 40% and if feasible it may be worthwhile to perform repeat cultures.Blood cultureInfection with Mycobacterium species became increasingly common as the incidence of HIV infection andAIDS increased. Up to 63% of HIV/AIDS patients with active TB disease have positive blood cultures. 139 Bloodculture should be the first step in the routine evaluation of HIV positive patients with suspected TB. 140TissueWhen non-invasive procedures have failed to provide a diagnosis, invasive procedures to obtain specimensfrom lung, pericardium, lymph nodes, bones and joints, bowel, etc. should be considered. 110 Specimenssubmitted in formalin are not suitable for microbiological smear and culture. In patients withhaematogenous or disseminated disease, bone marrow biopsy, lung biopsy and liver biopsy for histologicalexamination and culture can be useful. 110 Tissue is preferable to necrotic material or pus, as the lattercontain free fatty acids that are toxic to mycobacteria. 127 A caseous portion should be selected if possibleas the majority of organisms will be found in the periphery of a caseous lesion. 126 Pleural biopsy showsgranulomatous inflammation in approximately 60% of patients. 110 Minute amounts of biopsy material may beimmersed in a small amount of sterile saline to stop them drying out.Body fluidsPleural, peritoneal, synovial and pericardial fluids should be aseptically collected by aspiration or duringsurgical procedures and transported to the microbiology laboratory immediately. It should be noted thatdetection of AFB in smears of culture positive pleural fluids is extremely low at between 0 to 1% 141 and thesensitivity of nucleic acid amplification tests (NAAT) has been shown to be in the order of only 27 to 32% usingfully commercially available methods (see section on nucleic acid amplification tests). 1424.3 Specimen ProcessingMicroscopyAcid-fast microscopy is “the microscopic examination of stained smears for the presence of organismsthat retain the primary stain when the smear is decolourised with an acid alcohol solution”. Fluorescencestaining, 143 of clinical material using auramine-o or auramine-rhodamine is to be preferred over Ziehl-Neilson(ZN) staining because it is quicker and easier to read, 124;144;145 whilst the ZN is more appropriate in determiningmicroscopic morphology of bacilli in positive TB cultures. Factors affecting the sensitivity of smears are manyand include the staining technique, centrifugal force, decontamination technique used, the infecting species,reader experience and the prevalence of disease in the population being tested. 110;145;146Key points relating to microscopy:• Results should be available within one working day• Microscopy of clinical material (by either Auramine or Ziehl-Neilson (ZN)) is the easiest, most costeffectiveand rapid procedure for detecting mycobacteria-48-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• Both viable and non-viable organisms will stain acid fast• Microscopy has a sensitivity of approximately 90% for the most infectious cases of presumed TB.It therefore provides information to support respiratory isolation of patients and other infectioncontrol measures that prevent transmission of disease.• The grading of a smear can give some indication to the probability of a positive culture 124;147 (seetable 4.3)• The minimum number of bacilli necessary to produce a result has been estimated to be between5,000 and 10,000 per millimetre of sputum. The incremental yield of AFB from serial smearexamination has been shown to be 80-82% for the first, 10-14% for the second and 5-8% for thethird specimen. 124;147• 50-80% of patients with pulmonary TB will have positive smears 110• It is a useful tool for initiating treatment and monitoring the progress of anti-TB drug therapy• Fluorescence microscopy is more sensitive and as specific as conventional AFB microscopy 148• A minimum of 75 fields (250x) or 300 fields (1000x) should be examined by fluorescence and ZNrespectively 145• Re-examination of negative smears from specimens with positive culture can dramatically decreasea laboratory’s rate of false negative smears 144• Supervisory review of doubtful results in newly diagnosed patients can markedly decrease theincidence of false positive smears 144;145• Optimal results for sputum are obtained when auramine phenol stain is applied to a liquefied,concentrated sample and examined before the decontamination process 149• In laboratories with good expertise the predictive value of a positive smear can be as high as 90%and the predictive value of a negative smear 96% (based on good quality specimens) 144• The laboratory should participate in an external quality assurance scheme e.g. UK NEQAS AFBscheme.Table 4.3: Relationship of acid-fast smear and culture yieldNo. of AFB seen by staining method and magnificationReport ZN stain FluorochromeX 1,000 X 250 X 450Estimatedconcentration ofbacilliProbability of aculture positiveresultDoubtful;repeat1-2/300F 1-2/30F 1-2/70F 5,000-10,000 50%1+ 1-9/100F 1-9/10F 2-18/50F About 30,000 80%2+ 1-9/10F 1-9/F 4-36/10F About 50,000 90%3+ 1-9/F 10-90/F 4-36/F About 100,000 96.2%4+ > 9/F >90/F >36/F About 500,000 99.95%DecontaminationMany of the specimens sent for the isolation of Mycobacterium tuberculosis are contaminated withcommensal flora originating from the specimen site. This is particularly true of specimens from therespiratory and genitourinary tracts. Sodium hydroxide is the most common decontaminating agent usedin mycobacteriology. A contamination rate of between 2% to 5% is deemed acceptable. 115 An incidence ofless than 2% may suggest excessive decontamination and above 5% may suggest that cultures which mightcontain mycobacteria may be overgrown by commensal organisms. 110Samples from cystic fibrosis (CF) patients present a significant problem in that Pseudomonas aeruginosa,isolated from approximately 80% of CF patients can hinder and even prevent the recovery of-49-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCMycobacterium tuberculosis. 150 A two-step approach is advised where samples are initially decontaminatedwith N-acetyl-L-cysteine NaOH (NALC/NaOH) and only those samples which remain contaminated aresubjected to a second round of decontamination with NALC/NaOH and oxalic acid. Results suggest thatthis protocol could improve the recovery of mycobacteria from heavily contaminated specimens. 151CultureCulture is the bedrock and most reliable tool for the diagnosis of TB 152 and has a detection limit of 10 1to 10 2 viable organisms. 124 It is essential so that isolates are available for susceptibility testing, the resultsof which are necessary for the proper management of the patient. A confirmed case of TB is a case withculture confirmed disease due to M. tuberculosis complex. 23Isolates are also necessary in genotyping studies which are required for epidemiological investigationsand tracking laboratory cross-contamination. 153 Mycobacterium tuberculosis is a slow growing bacteriumand special media and procedures, not required for the culture of other organisms, are necessary. 127 Agarbased and egg based media, Middlebrook broths or solid media, the “traditional” methods of culture,have been superseded by the semi automated Bactec 460 and more recently by the continuous automatedmonitoring in liquid culture techniques (CAMLiC) 154 e.g. the Bactec MGIT960 TM , MB/BacT Alert 3D ‐TM andthe VersaTREK TM systems. These are now the basis of the “gold standard” in the isolation, culture anddefinitive diagnosis of mycobacterial disease.Each of the Bactec 460TB and CAMLiC systems has advantages and disadvantages and the choice ofsystem is often based on non-microbiological factors, e.g. size of equipment, quality of manufacturer’sservice and maintenance or in-built electronic data management systems. The microbiological factorsinclude:• Sensitivity of the detection system• Performance in recovery of Mycobacterium tuberculosis complex (MTC) and non-tuberculousmycobacteria (NTM)• Speed to positivity• Ability to perform susceptibility tests to anti-mycobacterial drugs and• Chemical agents, safety and cross-contamination.It is emphasised that in order to get optimal recovery of mycobacteria from clinical specimens usinga CAMLiC system, a combination of liquid and solid media is essential especially in non-specialisedlaboratories with a low incidence of M. tuberculosis. 155-157Recommendation:It is recommended that solid media be used in combination with a liquid culture system.Nucleic acid amplification tests (NAAT)CDC has produced an updated algorithm which offers useful guidance on the use of nucleic acidamplification tests (NAAT) 158 directly on specimens. CDC now recommends that NAAT should beperformed on at least one respiratory specimen from each patient with signs and symptoms of pulmonaryTB for whom a diagnosis of TB is being considered but has not yet been established, and for whom thetest result would alter case management or TB control activities such as contact tracing. 158Recommendation:All those wishing to undertake NAAT on suspected cases of pulmonary TB should seek advicefrom the local consultant microbiologist. It is recommended that NAAT should be madeavailable at the IMRL.-50-

1♦<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicians need to be aware of the limitations of these tests particularly in relation to the types ofspecimens analysed, the commercial system in use and the quality assurance programmes in place. 159-162Application of NAAT for the diagnosis of TB in sputa, CSF, and the detection of rifampicin and isoniazidresistance in primary and reference specimens should be provided only where there is an adequateinfrastructure, primarily sufficient space for a unidirectional workflow and dedicated equipment. 163Standardised methods with adequate and appropriate positive and negative controls should be used. 112A cost effective approach is to base these tests in laboratories in Ireland with expertise in molecularbiology. For procedural and economic reasons, NAAT might be impractical for laboratories with a smallvolume of testing. Referral of samples for NAAT to high-volume laboratories might be preferable toimprove cost-efficiency, proficiency and turnaround times. 1584.4 Processing of Positive CulturesIdentification methodsPhenotypic methodsMicroscopic and colonial morphology and other growth characteristics are useful in making a preliminaryidentification of an acid-fast bacillus. Colonies of the tubercle bacilli are described as being “rough, toughand buff” on solid media and colonies tend not to emulsify easily for making smears. MTC form serpentinechords in liquid media and are easily observed with ZN staining. These characteristics can lead to the mostrelevant tests being performed on each isolate to obtain identification. 127Probe techniquesProbe detection methods such as the AccuProbe, targeting ribosomal RNA gene, can identify the MTC,M. avium, M. intracellulare, M. avium complex (MAC), M. gordonae and M. kansasii. The technique isrelatively simple and the results are available within hours. The specificity has been shown to be 100% butthe sensitivity can vary within the species or species complexes. 124PCR and restriction endonuclease analysisIn 1993, Telenti 164 modified the Polymerase Chain Reaction (PCR)-Restriction Endonuclease Analysistechnique, subsequently known as the PRA method, to allow for the rapid identification of mycobacteriato the species level. The method has been used extensively for mycobacterial identification. The principaldisadvantage is that it is not commercialised and does not have US Food and Drug Administration (FDA)approval or carry CE3F markings.PCR and reverse hybridisation techniquesNew molecular biology techniques based on PCR and reverse hybridisation procedures have recently beenmarketed for mycobacterial identification. The hybridisation technique is performed on nitrocellulose stripsonto which probe lines are fixed in parallel. This format enables simultaneous detection and identificationof different mycobacterial species. At present, two systems with this design are commercially availablein Europe, the INNO-LiPA TM Mycobacteria v2 test, designed to amplify the mycobacterial 16S-23S rRNAspacer region, and the HAIN GenoType TM Mycobacteria assay, targeting the mycobacterial 23S rRNA. 165Both methods can be completed within two working days and allow precise identification of the majority ofmycobacteria usually isolated in clinical laboratories. They are expensive to perform but this can be offsetby the reduction in turnaround and labour times. These methods are available in the United States as FDAapprovedtests and bear the CE mark in the European Community.DNA sequencingThe availability of DNA sequencing technologies constitutes a great benefit for mycobacterialidentification, owing to the slow growth of these organisms. Recent improvements in automation of targetamplification and sequence analysis have led to the practical implementation of DNA sequencing in someclinical laboratories. 124 The technique requires expensive equipment and is best reserved for referencelaboratories.♦The CE marking (also known as CE mark) is a mandatory conformity mark on many products placed on the single market in theEuropean Economic Area (EEA).-51-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCMycobacterium tuberculosis complex (MTC)The Mycobacterium tuberculosis complex now consists of the following strains; M. tuberculosis sensustricto, M. bovis, M. bovis BCG, M. africanum 166 M. canettii 167 , M. bovis subsp. caprae 168;169 , M. microti 170 ,and M. pinnipedii. 171 All are known to cause infections in humans but they differ in their primary host,geographic range and pathogenicity. M. microti grows very slowly, often requiring up to 16 weeksincubation in liquid and solid culture media.Various methods may be used in order to differentiate members of the MTC. Specific inhibitors can beadded to a culture medium and growth or the lack of growth determined e.g. thiophen-2-carboxylichydrazide (TCH). M. tuberculosis is resistant to TCH while the other members of the complex are sensitive.Similarly, susceptibility to pyrazinamide is useful in differentiating M. bovis from other members of thecomplex in the majority of cases.More recently, a new commercially available DNA strip, GenoType MTBC, has been developed andevaluated. 172;173 Results demonstrated that the assay could unambiguously differentiate all of the MTC,with the exception of M. tuberculosis, M. africanum type II and M. canettii. The latter is considered to bea smooth variant of M. tuberculosis 167 and M. africanum II has not been successfully differentiated fromM. tuberculosis using molecular techniques suggesting that it likely represents phenotypically atypical M.tuberculosis strains. 174The GenoType MTBC was found to:• Enable a very rapid identification of the MTC• Fit into the work flow of a routine laboratory and• Be conducted in laboratories that do not carry out sophisticated biochemical tests fordifferentiation of the MTC.The results of these studies challenge the use of biochemical characteristics for classifying these organismsin diagnostic laboratories. 174Susceptibility testing of M. tuberculosisCDC has recommended that mycobacteriology laboratories work towards the goal of reporting first-linesusceptibility results for MTC within three to four weeks of receipt of the initial diagnostic specimen.Ideally, susceptibility results should be available within seven to 14 days after isolation of an MTC isolate.M. tuberculosis complex resistance is defined as “a decrease in sensitivity of sufficient degree to bereasonably certain that the strain concerned is different from a sample of wild strains of human type thathave never come into contact with the drug”. 175 Methods of drug susceptibility are not designed merelyto detect drug resistant mutants but are also to show that the great majority of bacilli in a culture are assusceptible to a given drug as one or more known susceptible strains. The object of susceptibility testing istherefore to determine whether an isolate is as likely to respond to standard therapy as one or more knownsusceptible strains. 127There are five methods in current use as outlined below:1. The absolute concentration method which is popular in some parts of Europe2. The proportional method also used in Europe and using Middlebrook 7H10 agar is the “goldstandard” method in the USA3. The disk diffusion method4. The resistance ratio method is used in the UK and those countries that are influenced by UKpractice and5. Commercially available systems, including the FDA approved Bactec 460TB, Bactec MGIT 960 andthe Versa TREK systems.The first four methods rely on conventional media and thus have the great disadvantage that there is along delay before results are available. In developed nations commercially available systems are used,so that results are made available more rapidly. 127 If resistance is detected the test may be repeated forconfirmation purposes, however, a report of the initial result should not be delayed while the repeattesting is being performed. The report should indicate that the drug resistance findings are preliminary andconfirmatory testing has been initiated.The first isolate of MTC obtained from every patient should be tested but also each isolate recovered-52-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCfrom each different anatomical site in the same patient. Susceptibility tests should be repeated if there isclinical evidence of failure to respond to therapy or if cultures fail to convert to negative after two monthsof therapy. For patients with resistant isolates, including resistance to the lower, critical concentration ofisoniazid, referral to or consultation with a specialist in TB treatment should be considered. 175The application of two commercially available DNA line probe assays, Genotype MTBDR TM and INNO-LiPA Rif TM to detect resistance to isoniazid and rifampicin (HAIN) or rifampicin alone (INNO LiPA) can beperformed when there is a strong suspicion of MDR-TB. Neither is 100% sensitive and results must beconfirmed by conventional testing. 176 In vitro susceptibility tests are very satisfactory for isoniazid, rifampicinand pyrazinamide and slightly less so for streptomycin. Results from ethambutol (E) and second line drugsmay vary depending on the test method used.Monitoring of anti-mycobacterial drug serum levelsThis may be occasionally required in suspected cases of non-compliance, malabsorption or toxicity. Thisservice can be provided by prior arrangement with the Antimicrobial Reference Laboratory in SouthmeadHospital, Bristol (see appendix 7 for contact details).Molecular typing of M. tuberculosisThere are currently three prominent methods for typing of M. tuberculosis strains. The current “goldstandard” is the IS6110-based restriction fragment length polymorphism fingerprinting. 177 This technique istechnically demanding and requires abundant amounts of growth of isolates. The remaining two methodsare polymerase chain reaction (PCR)–based genotyping tests, mycobacterial interspersed repetitive units(MIRU) typing 178 and spoligotyping. 179 In combination, the latter two tests (MIRU typing and spoligotyping)provide a highly discriminatory method to identify strains and will be used in the CDC TB GenotypingProgramme to enable rapid genotyping of isolates from every patient in the United States. 180 The IMRLintends to use MIRU typing in the first instance supported by spoligotyping.Genotyping of isolates can assist in the clinical and public health management of patients in severalsituations: 112• Genotyping allows evaluation of isolates with different patterns of drug susceptibility. Theoriginal organism may develop drug resistance during or after anti-TB therapy or the patientmay be re-infected with a different strain. The former may be due to non-adherence to therapyor reduced concentrations of anti-TB drugs as a result of malabsorption or drug interaction.The latter may be due to re-infection which would require further contact tracing investigationsas a public health issue.• Evaluation of an outbreak can be more clearly delineated or previously unrecognised contactsdetected• Genotyping can help to establish where resources might best be directed in a TB controlprogramme• On average 3% of patients from whom M. tuberculosis is apparently isolated in clinicallaboratories do not have TB. These positive cultures are due to cross-contamination. 1814.5 False Positive CulturesA review of reports of false positive cultures for M. tuberculosis showed that false positives were identifiedin 93% of studies that evaluated more than 100 patients. 181 The median false positive rate was 3.1%, with arange of 2.2% - 10.5%, and even higher rates (13.6%) have since been published. 182 The mechanism of falsepositive cultures can be many and include contamination of clinical equipment, clerical error and laboratorycross-contamination.For the purposes of further investigation, the source laboratories should not delay the forwarding ofpossible false positive M. tuberculosis complex isolates to the IMRL. The IMRL should perform DNAfingerprinting on all positive M. tuberculosis isolates and not delay the reporting of test results back to thesource laboratory. Confirmed false positives should be reported back to the clinicians as soon as possible.Clinicians should balance laboratory test results with their clinical judgement on whether or not a patienthas TB and inform the laboratory of any doubts.-53-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCLaboratory cross-contaminationOften the most significant laboratory feature is that the false positive culture is the only positive culture froma patient. However, single positive cultures also occur among patients who meet the clinical criteria for adiagnosis of TB. Prospective monitoring of single-positive cultures detected two outbreaks of laboratorycross-contamination that had not been recognised by clinicians or laboratory personnel. 181The quality assurance programme for mycobacteriology laboratories should include a plan for theidentification and review of possible false positive cultures. Criteria that might prompt a review shouldinclude a patient with a single culture positive specimen, cultures with a very low colony count on solidmedia and isolates with unexpected drug resistance.Possible causes of laboratory cross contaminationThe most common causes of laboratory cross-contamination include: 183• Contamination of multiple-use equipment for dispensing reagents• Aerosols• Splashing• Sampling equipment• Reprocessing of contaminated specimens and• Mislabelling.The general principle is to isolate each specimen completely so that there are no opportunities to transferan inoculum from one sample to another via pipettes, the lips, caps of tubes, splashes or common reservoirsof reagents or containers used for discarded materials. Examples of good laboratory practice include thefollowing: 184• Only bring the required numbers of items such as loops, swabs, pipettes, universal containers, etc.into the safety cabinet for each session of work• When using pipettes to deliver reagents, use a separate pipette for each specimen and each timethat the reagent bottle is entered• Individually wrapped sterile plastic pipettes should be used• Reagents, such as sodium hydroxide, should be supplied or prepared in individual sterile vials. Usea separate vial to add a reagent to each sample rather than dispensing it from a common container.• Remove and replace the cap from each specimen tube sequentially during the addition of reagentsto specimens, so that only one tube is open at a time and so that tube caps do not becomeinterchanged• Avoid spills and splashes when decanting supernatants• Clean and disinfect the exposed surfaces of the safety cabinet after each session of work• Where possible ensure that specimens are processed in the order of smear negative to smearpositive specimens. This requires the keeping of an up-to-date list of known smear positivepatients.• Process positive culture vials only when all the work on specimens has been completed for the day• At the end of the working day dispose of any used items in the cabinet and clean and disinfect theinterior surfaces of the safety cabinet• If possible, use a separate safety cabinet for specimens and all positive cultures, whether liquid orsolid 185• Investigate for possible cross-contamination when specimens in proximity to one another becomepositive. Cross-contamination may not occur with all samples in sequence, such that negativecultures occasionally may be found between positive cultures 183• Ensure that written procedures for the processing of cultures include detailed instructions and thatstaff have a very good understanding of the rationale for all aspects of the procedure.4.6 Interferon Gamma Release Assays (IGRA)The TST is a long established test that uses a relatively crude mixture of antigens from M. tuberculosis todetect the immune response to infection with M. tuberculosis (past or present). As a result false positivereactions can occur because of previous BCG vaccination or sensitisation to non-tuberculous mycobacteria.It has many limitations and requires well-trained personnel to both administer and interpret the test(see chapter 2).-54-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCThe immune response to infection with M. tuberculosis is predominantly a cell mediated immune (CMI)response. As part of this response, T-cells are sensitised to M. tuberculosis antigens. Activated effectorT-cells produce a cytokine called Interferon gamma (IFN- Υ ) when stimulated by these antigens. Laboratoryblood tests have been developed that detect this release of gamma interferon and are collectivelyknown as interferon gamma release assays (IGRA). The use of selected antigens for the M. tuberculosiscomplex improves specificity by reducing cross-reactivity to the BCG vaccine and to many environmentalmycobacteria. 186Two separate panels of antigens which simulate the well characterised proteins ESAT-6 and CFP10, areused to optimise the sensitivity of the T-SPOT.TB test, while the QuantiFERON-TB® Gold In-Tube (IT)method additionally incorporates a third antigen, TB7.7 (p4). The T-SPOT.TB and the QuantiFERON-TBGold® IT are tests for M. tuberculosis complex infection (including disease) and are intended for use inconjunction with risk assessment, radiography and other medical and diagnostic evaluations.T-SPOT.TB (Oxford Immunotec)T-SPOT.TB is a simplified variant of the enzyme-linked immunospot (ELISPOT) assay technique. The assayis designed for the detection of effector T-cells that secrete the cytokine in response to stimulation byantigens specific for M. tuberculosis. 187-190Limitations of the TSPOT.TBAccording to the manufacturer:• While ESAT-6 and CFP10 antigens are absent from BCG strains and from most environmentalmycobacteria, it is possible that a positive result from the T-SPOT.TB assay may be due to infectionwith M. kansasii, M. szulgai or M. marinum. Alternative tests would be required if these infectionsare suspected• Variation to the stated pipetting and washing techniques, incubation times and/or temperaturesmay influence the actual results obtained and should be avoided• Blood must be collected and progressed into the assay within eight hours• T-SPOT.TB should be used and interpreted only in the context of the overall clinical picture• A negative test result does not exclude the possibility of exposure to or infection with M.tuberculosis• Individual users should validate their procedures for collection of PBMCs, enumeration of PBMCsand choice of suitable media to support T-cell functionality during the primary incubation stage ofthe assay and• Failure to adhere to the recommended incubation time may lead to an incorrect interpretation ofthe result.QuantiFERON-TB Gold®- In-Tube (IT)QuantiFERON-TB Gold®- In-Tube (IT) (Cellestis, Victoria, Australia) is an in vitro diagnostic test using apeptide cocktail simulating ESAT-6, CFP-10 and TB7.7(p4) proteins to stimulate cells in heparinised wholeblood. Detection of IFN- Υ by enzyme-linked immunosorbent assay (ELISA) is used to identify in vitroresponses to these peptide antigens that are associated with M. tuberculosis complex infection.Limitations of the QuantiFERON-TB Gold® In-Tube (IT)According to the manufacturer:• The magnitude of the measured IFN- Υ level cannot be correlated to the stage or degree ofinfection, level of immune responsiveness or likelihood for progression to active disease• A negative QuantiFERON-TB Gold® IT result does not preclude the possibility of M. tuberculosisinfection or TB disease: false-negative results can be due to the stage of infection (e.g. specimenobtained prior to the development of cellular immune response), co-morbid conditions whichaffect immune functions, incorrect handling of the blood collection tubes following venepuncture,incorrect performance of the assay or other immunological variables• A positive QuantiFERON-TB Gold® IT result should not be the sole or definitive basis fordetermining infection with M. tuberculosis. Incorrect performance of the assay may cause falsepositive responses. Diagnosing or excluding TB disease and assessing the probability of LTBI,requires a combination of epidemiological, historical, medical and diagnostic findings that shouldbe taken into account when interpreting QuantiFERON-TB Gold® IT results-55-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• A positive QuantiFERON-TB Gold® IT result should be followed by further medical evaluation anddiagnostic evaluation for active TB disease (e.g. AFB smear and culture, chest X-ray)• While ESAT-6, CFP-10 and TB7.7 (p4) are absent from all BCG strains and from most known nontuberculousmycobacteria, it is possible that a positive QuantiFERON-TB Gold® IT result maybe due to infection by M. kansasii, M. szulgai or M. marinum. If such infections are suspected,alternative tests should be investigated.Sensitivity and specificity of IGRAThe lack of a gold standard for the diagnosis of LTBI makes it difficult to estimate the sensitivity orspecificity of IGRA or TST. Most studies use newly diagnosed active TB as a surrogate for LTBI but thereis an inherent problem with this, in that the cell-mediated immune response being measured must havefailed, to some extent, in any person with active disease. It has been well documented that in patientswith active infection the cell-mediated immune response is often diminished and this possibly explains thefinding that all three tests, but particularly TST, has sub-optimal sensitivity. 61;191-193 Of the three, the T-SPOT.TB was found to have the highest sensitivity and this correlates well with studies of immunocompromisedpatients that have shown T-SPOT.TB to have better sensitivity than TST. 194-196Other studies compared IGRA and TST among contacts categorised into clinically defined gradients ofexposure and sought to measure the agreement or discordance between the three. However, this is limitedby differences in the degree and categorisation of exposure. The prevalence of positives was found to besimilar for the most exposed groups but the TST had a greater prevalence of positives in the least exposedgroups. Discordance was shown to be higher in persons with BCG vaccination, especially those vaccinatedat age two years or older. 63;197;198Despite the variability in studies to date the most consistent finding has been the high specificity ofIGRA. This is most likely due to the fact that IGRA use antigens that are not found in BCG or most nontuberculousmycobacteria. To date there have been insufficient studies of IGRA performance amongchildren, immunocompromised persons and the elderly.4.7 Laboratory SafetyLevels of containmentThe principal legal framework governing safety in relation to biological agents is contained in the following:• The Safety, Health and Welfare at Work Act 2005• The Safety, Health and Welfare at Work (General Application) Regulations 2007 (S.I. No. 299 of2007)• The Safety, Health and Welfare at Work (Biological Agents) Regulations, 1994 as amended in 1998(S.I. No. 146, 1994, and S.I. No. 248 of 1998).These give effect to the European Council, Biological Agents Directives.Official copies of the legislation can be purchased from the Government Publications Sale Office, Sun AllianceHouse, Molesworth Street, Dublin 2. Tel. No: 01-6476000 or copies can be downloaded fromwww.irishstatutebook.ie.The following containment measures in the Seventh Schedule (Safety Health and Welfare at Work (BiologicalAgents) regulations, S.I. No. 146, 1994) of the legal framework are compulsory:• Extract air to the workplace are to be filtered using HEPA• Access is to be restricted to nominated workers only• There must be specified disinfection procedures• Effective vector control e.g. rodents and insects• Surfaces (bench and floor) impervious to water and easy to clean• Surfaces resistant to acids, alkalis, solvents and disinfectants• Safe storage of a biological agent and• Infected material is to be handled in a safety cabinet (class 1 or class 2) or other suitable-56-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCcontainment.Although the Seventh Schedule recommends the following points, the National TB Advisory Committee isproposing that these recommendations outlined below should be considered compulsory.• The workplace is to be separated from any other activities in the same building• The workplace is to be sealable to permit disinfection• The workplace is to be maintained at an air pressure negative to atmosphere• An observation window, or an alternative, is to be present, so that occupants can be seen and• A laboratory is to contain its own equipment.The decision to make this proposal has been influenced by looking at best international practice inrelation to the items that are recommended. In the UK, the Control of Substances Hazardous to Healthregulations 1994 (COSHH) implements the EC Biological Agents Directive. The Advisory Committee onDangerous Pathogens (UK) (ACDP) originally published the Categorisation of biological agents accordingto hazard and categories of containment (4 th edition) 1995. 199 This guidance has now been replaced by Themanagement, design and operation of microbiological containment laboratories, 2001. 200 This publicationcomplements the Health and Safety Commission’s Health Service Advisory Committee’s (HSAC) guidanceon Safe working and the prevention of infection in clinical laboratories and similar facilities 201 and the ACDPpublication Biological agents: Managing the risks in laboratories and healthcare premises. 202 Under thisguidance the above recommendations are compulsory.In the USA, laboratories performing functions at ATS level 2 or 3 must use Biosafety Level 3. Biosafety level3 is very similar to Containment Level 3 (CL3) and the above recommendations are included as rules. 114;203Finally, a CL3 Laboratory will fail to achieve accreditation with Clinical Pathology Accreditation (UK) Ltd ifthese recommendations are not in place.Recommendation:Recommendations in the Seventh Schedule of the S.I. No. 146/1994 Safety, Health andWelfare at Work (Biological Agents) Regulations 1994 should be interpreted as mandatory inrelation to working with M. tuberculosis complex.TransportationThe transport of infectious substances by road, rail, sea and air are each the subject of internationalregulation, whose whole description is beyond the remit of these guidelines. The relevant legislation inIreland for transport by road is the “Carriage of Dangerous Goods by Road” Regulations 2007 StatutoryInstrument No. 288 of 2007 204 and the 2007 ADR regulations. 205SpecimensBiological substances that have been correctly classified as UN No. 3373 which are packaged and markedin accordance with packaging instruction P650, are not subject to any other requirements of the 2007 ADRregulations. This implies that provided the correct packaging is used, there is no requirement for any ADRdocumentation or for the requirement to have specially marked and equipped vehicles or trained drivers.In summary, any method of transportation can be used to transport patient specimens by road onceproperly packaged and labelled.CulturesFor transport purposes, pathogens are assigned to two categories, A and B. Category A includes thehigher risk infectious microorganisms such as M. tuberculosis complex but only when it is present as aculture. Nevertheless, when cultures that are being transported by road are intended for diagnostic orclinical purposes (not research), they may be classified as infectious substances of Category B. Infectioussubstances in Category B shall be assigned to UN No. 3373 and the proper shipping name of UN No. 3373-57-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCis “BIOLOGICAL SUBSTANCE, CATEGORY B”. These are transported in accordance with ADR packagingregulations P650.However, at the time of publication of this document, when cultures of M. tuberculosis complex arebeing transported by air or sea they must follow the International Air Transport Association (IATA) andthe International Maritime Dangerous Goods (IMDG) regulations, that currently assign M. tuberculosisto Category A and they must be transported as UN No. 2814 “INFECTIOUS SUBSTANCE AFFECTINGHUMANS” and packaged in accordance with packing instruction P620. 205 This is most easily achieved byusing an approved and licensed courier.M. tuberculosis complex outside the CL3 laboratoryIt is worth noting that M. tuberculosis has been recovered from many body sites. 206-209 It follows thereforethat appropriate risk assessments with regard to M. tuberculosis are carried out when processing samplesfor other pathogens in other parts of the laboratory. This is especially so when an extended incubation timeis applied to recover fastidious pathogens. The observation that M. tuberculosis can be grown within sixdays on blood agar and that blood agar is at least as efficient as Lowenstein Jensen medium in recoveringM. tuberculosis from respiratory and lymph node aspirates must be considered when performing riskassessment analysis for other procedures in the microbiology laboratory. 210 Respiratory specimens, inparticular, may contain viable M. tuberculosis organisms and there are recommendations that these shouldbe analysed in a CL3 facility. 199;211Recommendation:All relevant legislation (national and international) for the transport and handling of specimensand cultures for tuberculosis should be strictly adhered to at all times.Molecular testingTests involving molecular methods do not require CL3 practices after the organism has been rendered nonviable.This is normally achieved through the application of heat. Some systems have been shown not torender the cultures completely unviable and therefore a laboratory must be able to definitively state anddemonstrate over time that any protocol in use for extracting mycobacterial DNA/RNA has succeeded inrendering the sample non-infectious before its removal from a CL3 facility. Methods which have producedconsistent killing of all mycobacterial species tested are those by which the tubes were fully immersed inboiling water or within a forced-hot-air oven set at 100 o C. 212-214AuditThere should be regular safety audits of the CL3 premises and processes.4.8 Quality AssuranceModern laboratory practice necessitates participation in both an internal and an approved external qualityassurance scheme e.g. United Kingdom National External Quality Assessment Service (NEQAS). Qualityassurance is a system that monitors and improves the efficiency and reliability of the laboratory service bypaying attention to detail at every step. There are three phases to the process as follows:Pre-analytical activities• How the test is ordered• Specimen collection procedures• Transport to the laboratory• Specimen handling and storage and• Completeness of patient information.-58-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAnalytical activitiesIn the laboratory quality assurance procedures guide and monitor all related activities including:• Instrument maintenance and operation• Test reagents• Personnel and• Actual test performance.Post-analytical activitiesWork quality continues to be monitored in areas such as:• Report sent to the appropriate party• Timely reporting of data and• Immediate reporting of positive results.Essential components of a quality assurance programme are:• Quality control• Quality improvement• Proficiency testing.A quality control system is essential for the effective and systematic monitoring of the performance ofbench work against established limits of acceptable performance. It ensures that the information generatedby the laboratory is accurate, reliable and reproducible. Effective monitoring is carried out through regularaudit at all levels in the process. Proficiency testing is essential and can be undertaken by participation inexternal quality control schemes such as NEQAS. Quality assurance is an essential component in achievingaccreditation to ISO or CPA UK Ltd standards.Recommendation:Laboratories should participate in internal and external quality assurance schemes for all testsperformed.-59-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC5. Clinical ManagementThe cornerstone of an effective TB control programme is prompt and accurate diagnosis, effectivetreatment and identification and appropriate management of contacts. The management of contacts isdealt with in chapter 8. This requires a multidisciplinary team approach involving clinicians, public healthstaff, the laboratory and pharmacists.5.1 DiagnosisGeneral practitioners and all other medical staff should maintain a high index of suspicion in relation to TB.CDC recommends that patients in the following situations should be evaluated for TB: 215• Any patient with a cough of ≥ 3 weeks duration with at least one additional symptom, includingfever, night sweats, weight loss or haemoptysis• Any patient at high risk of TB4F1ϒ with an unexplained illness, including respiratory symptoms of ≥ 3weeks duration• Any patient with HIV infection and unexplained cough and fever• Any patient at high risk of TB with a diagnosis of community-acquired pneumonia who has notimproved after seven days of treatment and• Any patient at high risk for TB with incidental findings on chest X-ray suggestive of TB even ifsymptoms are minimal or absent.Recommendation:All persons with an otherwise unexplained productive cough lasting three or more weeks withat least one additional symptom, including fever, night sweats, weight loss, or haemoptysisshould be evaluated for tuberculosis. 25 This will include clinical, radiological and bacteriologicalexaminations.Recommendation:All cases of suspected active TB should be referred to a TB clinic and have a clinicalassessment at the next available clinic. 216 If immediate evaluation is required, consult withthe clinical team regarding the need for more urgent clinical assessment. The managementof suspect TB cases can be undertaken in collaboration with the clinical team (respiratory orinfectious diseases) who will advise on sputa collection and the clinical management (includingcommencement of therapy, if the sputa are positive for AFB), until the next clinic appointment.Where pulmonary TB is suspected, a clinical evaluation including examination should be undertakenpreferably by a respiratory physician or infectious disease consultant with appropriate training in themanagement and treatment of TB. The evaluation should include an interview conducted in the patient’sprimary language with the assistance of qualified medical interpreters, if necessary.Diagnostic investigations should include chest X-ray, sputum smear microscopy and culture. All personswith chest X-ray findings suggestive of TB should have sputum specimens submitted for microbiologicalexamination. 25 Culture for M. tuberculosis complex (MTC) is considered the gold standard for diagnosis.Specimens may need to be obtained by sputum induction, broncheoalveolar lavage (BAL) or gastric lavageparticularly in children 77 (see chapter 4 on laboratory diagnosis).ϒPatients with one of the following characteristics: recent exposure to an infectious case; history of a positive test result formycobacterum tuberculosis (MTB) infection; HIV infection; injection or non-injection drug use; foreign birth and immigration in ≤5 years from high endemic region (TB rate ≥ 40/100,000 per annum); residents and employees of high-risk congregate settings;membership of a medically underserved, low-income population; or a medical risk factor for TB e.g. diabetes, immunocompromisedpatients.-60-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAll patients (adults, adolescents and children who are capable of producing sputum) suspected of havingpulmonary TB should ideally have three sputum specimens obtained for microscopic examination. Whenpossible at least one early morning specimen should be obtained. 25 The recommendations in chapter 4 onlaboratory diagnosis should be implemented in this regard.A sputum smear positive patient has a minimum of one sputum specimen positive for AFB by microscopy. 24The diagnosis of sputum smear negative pulmonary TB should be based on the following criteria:• At least three negative sputum smears (including at least one early morning specimen)• Chest X-ray findings consistent with TB and• Lack of response to a trial of broad-spectrum antimicrobial agents. 25As fluoroquinolones are active against M. tuberculosis complex and thus cause transient improvement inpersons with TB, they should be avoided. For such patients, if facilities for culture are available, sputumcultures should be obtained. In persons with known or suspected HIV infection, the diagnostic evaluationshould be expedited. 25An assessment of the likelihood of drug resistance based on history of prior treatment, exposure to apossible source case having drug-resistant organisms and the community prevalence of drug resistanceshould be obtained from all patients.In an era of increasing drug resistance every effort should be made to obtain bacteriological diagnosis inorder to obtain drug susceptibility data. This is also critical for obtaining molecular typing data essentialfor contact tracing and TB control programmes. For patients in whom drug resistance is considered tobe likely, culture and drug susceptibility testing for isoniazid, rifampicin, ethambutol, pyrazinamide andstreptomycin should be performed promptly. 25Where extrapulmonary TB is suspected, specimens from the suspected sites of involvement shouldbe obtained for microscopy, culture and histology. 25 The NICE guidelines suggest various site-specificinvestigations for the diagnosis of extrapulmonary TB (see table 5.1). 26CDC now recommends that NAAT should be performed on at least one respiratory specimen from eachpatient with signs and symptoms of pulmonary TB for whom a diagnosis of TB is being considered buthas not yet been established and for whom the test result would alter case management or TB controlactivities such as contact tracing. 158 All those wishing to undertake NAAT on suspected cases of pulmonaryTB should seek advice from the local consultant microbiologist (see chapter 4 on laboratory diagnosisof TB).-61-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 5.1: Suggested site-specific investigations in the diagnosis of extrapulmonary TB 26Site Imaging Biopsy CultureLymph node Node Node or aspirateBone/jointPlain X-ray and CT scanMRISite of diseaseBiopsy or para-spinalabscessSite or joint fluidGastrointestinalUltrasoundCT abdomenOmentumBowelBiopsyAscitesGenitourinaryIntravenous urographyUltrasoundSite of diseaseEarly morning urineSite of diseaseEndometrial curettingsDisseminatedCT thoraxUltrasound abdomenLungLiverBone marrowBronchial washLiverBone marrowBloodCNSCT scanMRITuberculomaCerebrospinal fluid (CSF)Skin Site of disease Site of diseasePericardium Echocardiogram/MRI Pericardium Pericardial fluidCold/liverabscessUltrasound Site of disease Site of diseaseReproduced with kind permission from Tuberculosis: Clinical Diagnosis and Management of Tuberculosis, and Measures for itsControl. National Institute for Health and Clinical Excellence (2005) London: Available at www.nice.org.uk/CG33.ChildrenThe diagnosis of TB in children can be difficult because of non-specific symptoms and infrequentisolation of the organism. WHO recommends that diagnosis should be based on a careful history, clinicalexamination, and relevant investigations including tuberculin skin test, chest X-ray and sputum smearmicroscopy. 217 Caution should be used when interpreting chest X-ray changes in children (and particularlyso in very young children), as changes are less specific than in adults. The approach to be taken should bediscussed with the consultant radiologist.The diagnosis of intrathoracic (i.e. pulmonary, pleural and mediastinal or hilar lymph node) TB insymptomatic children with negative sputum smears should be based on the finding of chest X-rayabnormalities consistent with TB and either a history of exposure to an infectious case or evidence of TBinfection (positive TST). For such patients, if facilities for culture are available sputum specimens should beobtained (by expectoration, induced sputum or gastric washings) for culture (chapter 4). 255.2 Supervision of TB TreatmentRecommendation:Treatment of TB should be directed by a consultant respiratory physician/consultant ininfectious diseases with appropriate training in the management and treatment of TB.Drug-resistant TBTreatment of patients with drug-resistant TB is complicated. The drugs used are toxic and expensiveand the outcome is not always successful in inexperienced hands. Treatment should always be directedby a consultant respiratory physician/consultant in infectious disease with appropriate training in the-62-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCmanagement and treatment of TB. Treatment should be in line with the International Standards for TB Care(ISTC) (appendix 8) and should be given for at least 18 months. 25ChildrenChildren with TB disease should be treated and managed by a consultant paediatrician with appropriatetraining in the management and treatment of TB in children. In areas where a consultant paediatrician withappropriate training is not available, the committee recommends joint supervision of such patients by arespiratory physician/consultant in infectious disease and the diagnosing consultant paediatrician.5.3 Role of Public Health Staff in Clinical ManagementUnder the Infectious Disease Regulations 2003, all TB cases (confirmed or presumed) are statutorilynotifiable to the medical officer of health (MOH). 21 The role of public health doctors includes theidentification of contacts of TB cases and arrangement of appropriate investigations (symptomquestionnaire, tuberculin testing, chest X-ray, sputum examination) and chemoprophylaxis. Contacts inreceipt of chemoprophylaxis are reviewed on a monthly basis or more frequently if indicated.When a TB case occurs in a healthcare setting, effective contact tracing requires liaison between publichealth services, hospital infection prevention and control and occupational health services. Coordinationof contact tracing is most appropriately led by hospital infection prevention and control (vis. consultantmicrobiologist) in those healthcare settings where this is in place. This will include the initial alerting ofpublic health and occupational health services. In all other healthcare settings, coordination should beundertaken by the public health service.Compliance with treatment is one of the most important determinants of treatment outcome and asignificant aspect of the work of public health staff (doctors and nurses) is to develop strategies to improvecompliance. Public health doctors also work with treating clinicians, public health nursing staff andpharmacists in the management of patients who may require DOT. They also have a role in the ongoingeducation and training of other health professionals, both within the hospital setting and within thecommunity.Recommendation:There should be active case management with a dedicated case manager or health careprofessional who liaises with and follows the patient during the entire treatment course tomonitor and enhance adherence.Combined clinics attended by both respiratory physicians and public health staff have operated as modelsof good practice throughout the country for the diagnosis and treatment of TB and the evaluation ofcontacts. Ideally all TB clinics should be based on this model. There is a need for the physician, publichealth staff and the pharmacist to have a strong working relationship for the successful management andtreatment of TB.Recommendation:More widespread establishment of combined clinics attended by both respiratory physiciansand public health doctors for the diagnosis and treatment of TB (and LTBI) and the evaluationof contacts is recommended. Such clinics should be appropriately staffed with medical,nursing, pharmacy, administrative staff and medically qualified interpreters and should beintegrated with the hospital system.-63-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRole of the pharmacist in the management of TBIt is recommended that a pharmacist is a member of the clinical team and attends the combined clinicswhere they have an important role to play in: 1) dispensing of TB medications to patients and maintainingdispensing records; 2) providing appropriate written and verbal information to patients to enable themto understand and comply with their medication; 3) promoting and monitoring patient compliance withtheir medication regime; 4) screening for potential drug interactions, monitoring adverse drug reactionsand advising on their management, particularly for patients with MDR-TB and HIV-TB co-infection; 5)maintaining links with community and hospital pharmacy services where appropriate and 6) participating inresearch and audit.The committee also encourages the development and maintenance of regional collaborative TBcommittees throughout the country. These multidisciplinary committees can review regional epidemiologyand local strategies for the prevention and control of TB.5.4 Treatment of TuberculosisEffective chemotherapy taken over an adequate period of time is the guiding principle of treatment for allforms of TB (pulmonary and extrapulmonary). The objective of anti-TB therapy is to achieve a lifetime cureof the disease while preventing drug resistance. 30All patients (including those with HIV infection) who have not been treated previously for TB should receivean internationally accepted first-line treatment regimen using drugs of known bioavailability. 25Recommendation:Isoniazid (H) and rifampicin (R), with pyrazinamide (Z) and ethambutol (E) for the initial twomonths (intensive phase), followed by isoniazid and rifampicin for a further four months(continuation phase) is recommended in patients with sensitive strains of tuberculosis andwhere there are no contraindications.As susceptibility results are not available at the start of treatment, regimens can be adjusted as theseresults become available. Under certain circumstances the continuation phase may be extended beyondfour months.Because of the difficulties with increased pill burden/medication volume and difficulty in monitoring forE toxicity an initial three-drug (HRZ) regimen is often acceptable in children, who generally have a lowbacillary burden. For children for whom there are specific concerns regarding resistance or the presence ofCNS involvement, and for adolescents, an initial four-drug regimen should be used.-64-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendation:Six months of chemotherapy is usually adequate for drug-susceptible pulmonary TB (table5.2). However, clinical trials have shown that selected patients have a higher rate of relapsewith a six month regimen and may benefit from longer treatment. 77;128;218;219 Therapy should beextended to nine months in the following cases:• Patients who have drug-susceptible pulmonary TB with initial cavitation on chest X-ray andwhose sputum cultures remain positive after the intensive phase i.e. the first two months oftherapy• Other patients who are still culture positive at two months regardless of chest X-ray results• Patients whose treatment regimen did not include pyrazinamide in the intensive phase orwhose organism is resistant to pyrazinamide• Patients being treated with once-weekly isoniazid and rifampicin whose sputum cultureremains positive after the two month intensive phase of treatment. 77Recommendation:Follow-up sputum specimens for smear and culture should be obtained monthly in patientswith drug-susceptible pulmonary disease. Requests for more frequent testing should only beundertaken following discussion between the treating clinician and consultant microbiologist.For patients with isoniazid- and rifampicin-susceptible TB there is no need to examine sputummonthly once culture conversion is documented (i.e. two negative cultures taken at least twoto four weeks apart). 77 It is recommended that identification and sensitivities are repeated incases who are still culture positive at ≥ two months.Bacteriological monitoring i.e. culture at the end of treatment in confirmed cases is strictly recommendedto assess precisely that the patient has been cured. A negative sputum culture at the end of treatment isthe only conclusive evidence that the patient has been cured. 77EuroTB classifies treatment failures as patients who have culture or sputum microscopy remaining positiveor becoming positive again at the fifth month or later during treatment. 10 Patients who fail treatmentshould be assessed by a consultant respiratory/infectious disease physician with appropriate training in themanagement and treatment of TB for possible drug resistance and have therapy modified accordingly.In cases of extrapulmonary TB, the same regimens should apply, though in certain circumstances, treatmentmay need to be more prolonged e.g. TB meningitis, miliary/disseminated disease. In such cases, a longercourse of therapy is suggested, especially in children, in whom 2 months of at least three drugs in the initialphase and 10 months of two or more drugs in the continuation phase are recommended, assuming that theinitial isolate is fully drug sensitive. 30 In patients with extrapulmonary TB and in children, the response totreatment is best assessed clinically. Follow-up radiographic examinations are usually unnecessary and maybe misleading. 25M. bovis is invariably resistant to pyrazinamide and a three-drug nine month regimen is indicated (RHE 2+RH 7).Patients should be assessed monthly during the initiation phase and one to two monthly during thecontinuation phase of therapy, depending on their level of compliance, likelihood of treatment-relatedadverse events etc. (see appendix 5: TB therapy audit form).-65-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCA written record of clinical symptoms and examination, all medications given, adverse reactions, adherenceto treatment and bacteriological response should be maintained on all patients. 25 The assessment shouldinclude an interview conducted in the patient’s primary language with the assistance of qualified medicalinterpreters, if necessary.The prompt recognition and appropriate management of adverse drug reactions is an essential part ofthe treatment programme and clinicians, nurses and pharmacists responsible for drug therapy need to bewell acquainted with these reactions (table 5.2). Toxicity and hypersensitivity reactions require that theoffending drug(s) be discontinued. However, this should be accompanied by careful evaluation of thereaction and identification of the offending drug(s) to avoid unnecessary cessation of a first-line drug. 30If a DOT programme is employed, a three-times-weekly regimen may be used if acceptable to thepatient (table 5.2). Agents such as streptomycin, amikacin, quinolones, etc. should only be used underthe supervision of a consultant respiratory physician or consultant in infectious disease with appropriatetraining in the management and treatment of TB. Advice on potential drug interactions and adverseeffects should be sought from the pharmacist on the clinical team.-66-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 5.2. Dosages for primary medications used in the treatment of tuberculosisDrugMode of actionRoute ofadministrationDaily dose[max]3 Times aweekdose [max]2 Times aweekdose [max]Major adversereactions*IsoniazidBactericidalOral/IntramuscularChildren:5-10mg/kg 1Adults: 5mg/kg [300mg]Children:20mg/kgAdults:10mg/kg(range8-12mg/kg)[900mg]Children: 20mg/kgAdults: 15mg/kg(range 13-17mg/kg)[900mg]Hepatic enzymeelevations, hepatitis,rash, peripheralneuropathy, CNSeffects, increasedphenytoin levels,possible interactionwith disulfiramRifampicinBactericidalOral/IntravenousChildren: 10-20mg/kg 2Adults: 600mg(range8-12mg/kg)[600mg]Children: 10-20mg/kgAdults:600mg(range8-12mg/kg)[600mg]Children: 10-20mg/kgAdults: 600mg(range 8-12mg/kg)[600mg]Hepatic enzymeelevations, hepatitis,rash, fever,thrombocytopaenia,influenza-like syndrome,reduced levels ofmany drugs (includingmethadone, warfarin,hormonal forms ofcontraception, oralhypoglycaemic agents,theophylline, dapsone,ketoconazole, PIs, andNNRTIs)PyrazinamideBacteriostaticOralChildren:25mg/kg(range 20-30mg/kg)Adults: 25mg/kg (range 20-30mg/kg)[2.0g foradults andchildrenChildren:35mg/kg(range 30-40mg/kg)Adults:35mg/kg(range 30-40mg/kg)[3.0g foradults andchildrenChildren: 50mg/kg(range 40-60mg/kg)Adults: 50mg/kg(range 40-60mg/kg)[3.5g for adultsand childrenGastrointestinal (GI)upset, hepatotoxicity,hyperuricaemia, gout(rarely), arthalgias, rashEthambutolBacteriostaticOralChildren:20mg/kg(range 15-25mg/kg)[1.5g]Adults: 15-25mg/kg[2.0g]Children:30mg/kg(range 25-35mg/kg)Adults:30mg/kg(range 25-35mg/kg)[2.8g]Children: 40-50mg/kg[2.5g]Adults: 45mg/kg(range 40-50mg/kg)[3.6g]Decreased red-greencolour discrimination,decreased visual acuity,skin rashStreptomycinBactericidalIntramuscular/IntravenousChildren:15-30mg/kgAdults: 15mg/kg [1.0g]Children:15mg/kgAdults:15mg/kg[1.0g]Children: 15mg/kgAdults: 15mg/kg[1.0g]Auditory toxicity, renaltoxicity, hypokalaemia,hypomagnesaemia*All toxicities are not listed here. Full prescribing information should be checked in the package insert or pharmacology texts.-67-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 5.2. Contd.DrugRecommended regularmonitoringCommentsIsoniazid- Monthly clinical- Vitamin B 6(pyridoxine) 10mg/day may decrease peripheral neuritisevaluationand CNS effects and should be used in patients who are abusing- Liver function tests 3 alcohol, pregnant, breastfeeding infants on isoniazid, malnourished,or who have HIV infection, cancer, chronic renal or liver disease,diabetes, or pre-existing peripheral neuropathy- Aluminium-containing antacids reduce absorption- Drug interactions with several agentsRifampicinPyrazinamideEthambutolStreptomycin- Monthly clinicalevaluation- Complete blood cellcount including plateletsand liver function testsas indicated 3- Monthly clinicalevaluation- Liver function tests asindicated 3- Monthly clinicalevaluation- Check colour vision andvisual acuity monthly- Monthly clinicalevaluation- Audiometry, renalfunction, electrolytes,including magnesium- Orange discolouration may occur in contact lenses and bodysecretions such as tears and urine- Patients receiving methadone will need their methadone dosageincreased, by an average of 50%, to avoid opioid withdrawal- Interaction with many drugs leads to decreased levels of the coadministereddrug- May make glucose control more difficult in people with diabetes.- Contraindicated for patients taking most PIs and NNRTIs- Patients should be advised to use barrier contraceptives while onrifampicin- May complicate management of diabetes mellitus- Hyperuricaemia can be used as indicator of compliance- Treat increased uric acid only if symptomatic- Allopurinol increases level of pyrazinamide by inhibiting xanthineoxidase resulting in failure of allopurinol to lower serum uric acid- Optic neuritis may be unilateral; check each eye separately. Ifpossible avoid in children too young to undergo vision testing.- If patient develops visual complaints, refer for promptophthalmologic evaluation. May need to discontinue ethambutolwhile awaiting evaluation.- Ultrasound and warm compresses to injection site may reduce painand induration1World Health Organization (WHO), International Union against TB and Lung Disease (IUATLD), and British Thoracic Society (BTS)recommend 5mg/kg in children; Centers for Disease Control and Prevention (CDC), American Thoracic Society (ATS), InfectiousDisease Society of America (IDSA) and the American Academy of Paediatrics (AAP) recommend 10-20mg/kg2WHO, IUATLD, and BTS recommend 10mg/kg in children; CDC/ATS and the AAP recommend 10-20mg/kg3Liver function tests are indicated if baseline is abnormal or patient has risk factors for toxicityReproduced with kind permission from Tuberculosis, Clinical Policies and Protocols. New York City Department of Health and MentalHygiene (2008). Available at www.nyc.gov/html/doh/downloads/pdf/tb/tb-protocol.pdfRecommendation:To enhance compliance and to minimise potential problems from the development of drugresistance, it is strongly recommended that only combination tablets should be used.Syrup/tablet dosage should be rounded up or down to facilitate the prescription of easily given volumes/tablets. All cases of TB placed on the above regimens for active disease should be notified to the localpublic health physicians. In addition, the committee recommends routine audit of both inpatient andoutpatient care of TB.Care should be taken in writing prescriptions so that rifadin (contains rifampicin only) is not confused withrifinah (contains rifampicin and isoniazid) and rifater (contains rifampicin, isoniazid and pyrazinamide).-68-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCPyridoxinePyridoxine is often used in conjunction with anti-TB drugs to prevent side effects in the peripheral andcentral nervous systems. It is recommended that pyridoxine 10mg daily (20mg daily may be used if 10mgtablets are not available) should be prescribed for:• All adults, including pregnant women• Children who have poor nutrition and therefore are at risk of pyridoxine deficiency• Children who develop paraesthesia• Breastfeeding infants on isoniazid• A fully breastfed infant if the mother is on isoniazid, regardless of whether the infant is on anti-TBtreatment• In particular, those with pre-existing peripheral neuropathy diabetes, chronic renal or liver disease,52 77cancer, alcoholism, malnutrition, other immunosuppressive disorders or HIV.As there are no side effects to low dose pyridoxine, many centres routinely prescribe it to prevent thedevelopment of neuropathy. 30 However, it is not routinely prescribed in children except in the situationsmentioned above.MonitoringBaseline LFTs and a complete blood count including platelets and biochemistry panel (including creatinine)should be obtained from all patients prior to commencing TB therapy. Monthly follow-up blood testing isnot necessary if the baseline is normal unless a patient develops symptoms consistent with adverse drugreactions.Other relevant laboratory tests should be obtained according to the medications used and side-effectspresent (see table 5.2). For example, renal function and hearing may be affected by the aminoglycosidesand capreomycin; uric acid levels are affected by pyrazinamide. (Note: an increase in uric acid is not anindication to discontinue pyrazinamide as long as the patient remains asymptomatic). Thyroid functiontests should be performed for patients on para-aminosalicylic acid or ethionamide.Management of adverse reactions: hepatotoxicitySeveral anti-TB medications cause hepatoxicity (see table 5.2). In addition, concomitant use of TBmedications increases the risk of developing drug-induced liver damage. Despite these risks, the benefitsof TB treatment to the individual far outweigh the risks. Concomitant use of other known hepatotoxicagents should be avoided if possible during anti-TB treatment especially in patients with underlying liverdisease. A consultant with expertise in TB should always be consulted when treating a patient withactive TB disease with documented hepatotoxicity.Follow-upIn most cases of TB, it is desirable to review the patient at six months after completing treatment asrelapses, should they occur, tend to present within this time. Unless there is a specific cause for concern thepatient may be discharged at this time.Anti-TB regimens in pregnancyThe risk of untreated TB to a pregnant woman and her foetus is far greater than the risk of the toxic effectsfrom the drugs used in its treatment. 220 In a pregnant woman who has active TB disease as verified by apositive M. tuberculosis culture or who is highly suspected of having active TB it is essential that prompteffective treatment be administered. Very rarely, following risk assessment by and approval from thetreating clinician, treatment for suspected TB may be deferred until the end of the first trimester. This maybe done if the pregnant woman is very reluctant to take the treatment and meets all the following criteria:• Sputum smear negative for AFB• HIV-negative-69-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• No risk factors for HIV infection• Has no symptoms of TB i.e. cough, fever, weight loss or night sweats• Has no cavitation on chest X-ray. 77The use of isoniazid, rifampicin and ethambutol have been well studied during pregnancy and their useis safe in this setting. 221 The use of aminoglycosides (streptomycin, amikacin and kanamycin) and thepolypeptide capreomycin are contraindicated during pregnancy. 30;77 The effect of pyrazinamide on thefoetus is not known. However, if treatment is started after the first trimester, pyrazinamide should beincluded in the initial treatment regimen for the following women:• Women who are HIV positive• Women with behavioural risk factors for HIV infection but decline HIV testing• Women suspected of having MDR-TB.Despite the lack of data on pyrazinamide, WHO recommends its use at all stages of pregnancy for allpregnant women. 77Standard regimen for pregnant womenThe initial treatment regimen in pregnancy should consist of isoniazid, rifampicin and ethambutol unlessthere are absolute contraindications. 30 Pyridoxine 10mg daily (20mg daily if 10mg tablets are not available)is recommended for pregnant and breastfeeding women (unless the patient is already on a prenatal vitaminsupplement that contains the equivalent amount of pyridoxine).Pregnant women suspected or known to have MDR-TBUnlike the treatment of drug-susceptible TB, it is not possible to develop standardised protocols for thetreatment of known or suspected MDR-TB. As with all drug-resistant TB cases, expert consultation shouldbe sought with a respiratory physician or infectious disease consultant.Anti-tuberculosis medications in breastfeeding womenThe small concentrations of anti-TB drugs in breast milk are not toxic to the nursing newborn. Therefore,breastfeeding should not be discouraged for women who are HIV negative and who are planning to takeor who are taking isoniazid or other anti-TB medications. Furthermore, the low concentration of anti-TBmedications in breast milk should not be considered effective treatment for disease or for treatment ofLTBI in a nursing infant. Women who are HIV positive should not breastfeed because of the risk of HIVtransmission to the infant. 775.5 Inpatient or Outpatient ManagementMany patients do not require admission to hospital either for investigation or initiation of treatment for TB.However, a minority will be acutely ill and will require admission to hospital. These include:• Those with severe forms of TB such as: central nervous system (CNS) and meningeal TB, pericardialTB or disseminated or miliary TB• Haemodynamic instability• Severe haemoptysis• Severe debilitation with weight loss, severe cough, high fevers and inability to care for themselves• Advanced AIDS• Co-morbid medical conditions that require treatment in hospital. 77Other indications for admission include:• MDR-TB or XDR-TB• Toxicity from medication• Poor compliance-70-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• Social reasons e.g. having no fixed abode, alcohol or drug abuse, not ambulatory and needingprofessional home care e.g. home help• The need for isolation because of:o particularly vulnerable (immunosuppressed or children under five years of age who havenot been evaluated for LTBI and window period prophylaxis) household or other contactsoro living in a congregate setting such as a nursing home. 77Others will require admission to clarify the diagnosis.On a practical basis, young children will often require hospital admission to complete TB investigations.Recommendation:It is recommended that the supraregional TB centre at St. James’s Hospital and a numberof regional centres should have a small number of non-acute beds available to facilitate theinpatient care of patients who are non-compliant or have drug-resistant TB.The beds should be on the campus of an acute general hospital and each unit should have adequaterecreation and rehabilitation facilities. For patients who require inpatient supervision throughout the courseof their treatment, ‘stepdown’ beds in a non-acute facility may be appropriate when the patient isclinically stable.5.6 Adherence and Directly Observed Therapy (DOT)Treatment of TB is very effective. The International Standards for Tuberculosis Care state that anypractitioner treating a patient for TB is assuming an important public health responsibility. To fulfil thisresponsibility, the clinician must not only prescribe an appropriate treatment regimen but must also becapable of assessing the adherence of the patient to the regimen and of addressing poor adherencewhen it occurs. 25 The responsibility for successful treatment lies with public health in cooperation with thetreating physician. 30 However, patients should be involved in their treatment decisions from the onset andthe importance of adherence should be emphasised. 26In this context, it is essential that patients take their medication as prescribed by the consultant respiratoryphysician/consultant in infectious disease. Treatment completion is a fundamental principle of TB control.Failure to complete treatment can result in patient relapse, a potential to infect contacts and an increasedrisk of drug resistance. The most important reason for failure is that patients do not take the prescribeddrugs regularly or for long enough. 222 The importance of adherence is therefore central to establishinggood cure rates for TB and preventing the emergence of drug resistance. As the patient improves andfeels better, compliance may be more problematic.To foster and assess adherence, a patient-centred approach to administration of drug treatment basedon the patient’s needs should be developed for all patients. A central element of the patient-centredstrategy is the use of measures to assess and promote adherence to the treatment regimen and to addresspoor adherence when it occurs. Supervision and support should be gender-sensitive and age-specific.The measures should be tailored to the individual patient’s circumstances. 25 In this regard, the committeerecommends the appointment of a key worker/treatment supporter for each patient. TB services should-71-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCalso provide medically qualified interpreters and patient information in the relevant language. The NICEguidelines recommend the following interventions if a patient defaults from treatment: reminder lettersin the appropriate language, patient-centred interview and health education booklet; health educationcounselling; home visits; patient diary and random urine tests and other monitoring e.g. pill counts. 26Directly observed therapy (DOT)DOT is a way of helping patients to take their medicine for TB. A person receiving DOT will meet with ahealthcare worker/key worker everyday or several times a week at an agreed place e.g. the patient’s home,the TB clinic or other convenient location. The healthcare worker will observe the patient taking theirmedication at this place helping to ensure that higher treatment completion rates are achieved. Sometimessomeone in their family or a close friend will be able to help in a similar way to the healthcare worker.Blumberg et al have reported completion rates of between 85 and 90% using DOT. These compared withcompletion rates of 60% after self-administration of therapy. 219 In addition, the use of DOT has also beenshown to reduce the rate of drug resistance and relapse when compared to self-administered therapy. 223The key worker will be actively involved in the administration of DOT and should actively monitor andensure compliance. They should also be acceptable and accountable to the patient and to the healthsystem.However, the availability of DOT is currently limited and needs to be improved in the majority of HSEareas. Where universal provision of DOT is not feasible because of resource limitations, the followingcircumstances should be given priority:• Suspected or proven drug-resistant organisms• Treatment failure• Documented re-treatment disease• Injection drug users/homeless persons• Suspected non-adherence or previous non-adherence• HIV infection• Children• Psychopathology• Too ill to self administer• Smear positive for AFB 30;77;224Ormerod et al have shown that DOT may be selectively used when not all patients are being treated withDOT and at least 90% of patients complete treatment (no culture done at the end of treatment) or arecured (negative culture at the end of treatment). 224The establishment of a structured national DOT programme is vital for the effective management andcontrol of TB and in particular, for effective control of TB among foreign-born cases.Recommendation:Prioritising the establishment of a structured national DOT programme is recommended formore effective management and control of TB.This will require close coordination between the secondary care hospitals and the public health service.-72-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCStaff supervising DOT should be appropriately trained. The regimen should be determined by the treatingphysician in conjunction with the patient. In some cases, an intermittent regimen may be appropriate. Inothers, a daily regimen is more appropriate. See HSE South (Cork and Kerry) DOT referral form in appendix 9.In addition, procedures for monitoring compliance such as pill counts need to be established early in thetreatment of the disease. Blister packs labelled with each day’s TB medication will also facilitate compliance.Pharmacists should be involved in monitoring compliance. In order to monitor and improve compliance,the patient should receive their anti-TB medications from the same pharmacy on a monthly basis. Electronicrecords of each dispensing should be maintained and ongoing liaison between the pharmacist andprescriber is recommended. Medication must be easily accessible for the patient and ideally should beavailable at the diagnosing clinic/hospital.A directly observed therapy short-course strategy (DOTS strategy), the internationally recommendedapproach by WHO to TB control has been successfully implemented in many countries but requires carefulinstitution and monitoring. This comprises five components as follows: (i) political commitment withincreased and sustained financing; (ii) case detection through quality-assured bacteriology; (iii) standardisedtreatment with supervision and patient support; (iv) an effective drug supply and management system;and (v) a monitoring and evaluation system and impact measurement. 5 The committee recommendsendorsement of the WHO DOTS strategy at the highest level.Use of DOT in MDR-TB and XDR-TBIn all cases of MDR-TB and XDR-TB the use of DOT is recommended. A daily regimen is more appropriate.Use of DOT in childrenThree times weekly therapy is not generally recommended for children but twice or thrice weeklyadministration of rifampicin and isoniazid by DOT can be considered after completion of the initial twomonth period of treatment in selected circumstances.5.7 LegislationCompliance with medication is core to TB control. In practice, a subset of patients are noted who are noncompliantwith treatment and are resistant to any intervention in the community. Under Section 38 of theHealth Act, 1947 the MOH may order the detention and isolation of an infectious person until that personis no longer a probable source of infection. 225 Section 35 of the Health Act, 1953 amends the 1947 Act,directing that the order must be signed by the MOH and another registered medical practitioner. 226This legislation dates back to the 1940s and 1950s (1947 and 1953). It gives the power to detain noncompliantpatients but does not give the power to ensure that patients comply with treatment. Personalcommunication with HSE areas has highlighted a number of enforcement-related issues in recent timesprimarily with regard to treatment refusal, place of detention and personal rights. This legislation is currentlybeing reviewed by a HSE committee.-73-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC6. Infection Prevention and ControlThe extent and duration of measures required to prevent and control TB infection, depends upon theestimated degree of infectiousness of the patient, the response to treatment, the nature of the activitiesundertaken, and who will be exposed to the patient in the course of those activities.Risk factors for acquiring TB infectionThe risk of acquiring TB is determined by a number of factors such as the degree of infectiousness of thesource patient or the presence of predisposing medical conditions in contacts e.g. HIV infection, diabetes,alcoholism, drug addiction, immunosuppression and renal failure. The following features in the source casehave been shown to increase the risk of infection:• Close contact with the source case (section 8.5)• Duration of contact (the longer the contact the greater the risk)• Sputum smear positive• Presence of a productive cough• Delay in diagnosis• Open TB lesions requiring irrigation• Institutional contact with the source case (prisons, nursing homes, shelters, etc).6.1 Classification of Risk of Procedures in HealthcareHCWs are at risk of infection depending on their contact with patients and the clinical proceduresundertaken during care. These procedures have been categorised into high, medium and low risk activities.High risk- Cough inducing procedures (including sputum induction and bronchoscopy)- Autopsy- Pathology examination- Bronchoscopy- Designated TB laboratory procedures especially handling cultures of TBMedium RiskStaff whose work entails regular contact with the patient (e.g. nursing, physiotherapy, nursingattendants, cleaning staff, catering staff)Low riskStaff with minimal patient contact (e.g. administration, maintenance).6.2 Definition of an Infectious TB CasePatients aged 10 years and over with suspected or confirmed pulmonary or laryngeal TB should beconsidered infectious if any of the following are present and if they are not receiving therapy, have juststarted therapy or have a poor response to therapy 77;227-229• Are coughing• Are undergoing sputum inducing procedures• Have cavitations on chest X-ray• Are sputum AFB smear positive• Have suspected laryngeal involvement (i.e. hoarseness)-74-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCBAL AFB smear positive if any of the following are present:• Cavitations on chest X-ray• Suspected or confirmed MDR-TB• Admitted to a ward or living with immunosuppressed*** 1 individuals.The determination of infectivity of all other BAL smear positive patients should be considered on a case-bycasebasis (clinical/microbiology/public health input).Most children aged less than 10 years with suspected or confirmed TB are not infectious (chapter 8)however, they should be considered infectious if any of the following are present: 77• Cavitations on chest X-ray• Sputum smear positive (not BAL or gastric washings positive)• Suspected laryngeal involvement• Extensive pulmonary infection• Congenital TB and undergoing procedures involving oropharyngeal airway.In addition, patients with extrapulmonary TB in an open abscess or lesion should be considered infectiouswhen aerosolisation of drainage fluid occurs.When a patient with suspected or confirmed infectious TB is receiving healthcare, appropriate infection,prevention and control must be followed to protect employees and other patients from infection.The effective prevention and control of TB relies on:Administrative aspectsImplementation of Standard and Airborne Precautions.6.3 Administrative AspectsAdministrative aspects of the prevention and control of TB comprise early investigation, diagnosis andtreatment by:• A high level of suspicion amongst clinical teams and GPs• Local procedures and guidelines for the management of TB in acute hospitals and community careareas• Staff education and training on current guidelines and procedures• Informing the infection prevention and control team promptly of all suspected and confirmed casesof TB• Collaboration between laboratory, microbiological and clinical teams to ensure rapid testing ofspecimens for acid–fast bacilli (AFB).6.4 Standard PrecautionsStandard precautions are defined as follows: 230Standard precautions are a set of work practices that require all HCWs to assume that allblood, body fluids (except sweat), excretions and secretions from all patients in all settingsare potential sources of infection.***Immunosuppressed is defined as either due to disease or therapies e.g. HIV, individuals receiving >15mg prednisone or equivalentfor more than four week or other immunosuppressive agents for cancer, chemotherapeutic agents, anti-rejection drugs for organtransplantation and TNF-α antagonists or as defined by the attending consultant.-75-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCImplementation of standard precautions constitutes the primary strategy for the prevention of healthcareassociated transmission of infectious agents among patients and healthcare personnel. 230 Full details ofstandard precautions are available in appendix 10. 230Standard precautions include the following work practices and measures:• Occupational health programme• Hand hygiene• Personal protective equipment• Management of spillages of blood and body fluids• Appropriate patient placement• Management of sharps• Management of needle stick injuries and exposure to blood and body fluids• Management of waste and laundry• Safe injection practices• Respiratory hygiene and cough etiquette• Appropriate decontamination of reusable medical equipment• Appropriate decontamination of the environment.Certain transmissible infections require additional control measures to standard precautions to effectivelyprevent transmission. Infectious pulmonary and laryngeal TB require airborne precautions in addition tostandard precautions.6.5 Airborne PrecautionsFull details of Airborne Precautions are available in appendix 10. 230The following section outlines the elements of Airborne Precautions and how they apply to themanagement of a suspected or confirmed infectious TB case.Patient placementIsolation rooms with ventilationSpecially engineered rooms have been designed to limit the spread of certain transmissible infections thatare transmitted via air such as TB. Two designs are suitable for Airborne Precautions:1. Negative pressure isolation room with an ante room. This room has an air handling unitwhich ensures that the air in the room remains at negative pressure to the ante room and thehospital environment2. Neutral pressure design as detailed in HBN 04 Supplement 1. 231Air changes per roomIt is recommended that a minimum of six air changes per hour (ACH) is required for the protection of staff129; 232-234and visitors however, in new buildings 12 ACHs are advised.Isolation rooms can be designed for negative pressure use only but some may have an air handlingunit that can be switched from negative pressure to positive pressure depending on infection controlrequirements. These dual action rooms have been implicated in outbreaks when the incorrect airpressure was selected for a specific infection or patient. This design should not be used in new builds orrefurbishments.Monitoring of ventilation systemAirborne isolation rooms should be monitored continuously by the pressure differential between the roomand the surrounding ward. The monitoring system should alert staff of any failure. 235There should be:• Standard operating procedures (SOPs) in place for changing the air handling settings at wardlevel (if applicable)• SOPs in place for documenting the daily checks on the monitoring system at ward level• Regular engineering checks on the number of air changes and air direction (smoke tests) toensure compliance with best practice 234;235• Regular training for staff in their use• Changing of HEPA filters as directed by manufacturers’ instructions (if applicable).-76-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCMore detailed information regarding the operation of these rooms is available in the UK Department ofHealth’s document on “The prevention and control of tuberculosis in the United Kingdom: UK guidanceon the prevention and control of transmission of 1. HIV-related tuberculosis 2. drug-resistant, includingmultiple drug-resistant, tuberculosis, 1998”, “Hospital and community acquired infection and the builtenvironment-design and testing of infection control rooms. Journal of Hospital Infection 2007 published byWalker et al and HBN 04 Supplement 1. 231;234;235The design of airborne isolation rooms planned for new buildings or major refurbishments should be basedon the neutral pressure design, as detailed in HBN 04 Supplement 1 rather than a “switchable” negative/positive pressure design. 236It is important to note that no ventilation system will function correctly if the doors or windows are open.Sputum induction and aerosol-generating procedures• Sputum induction is used to obtain sputum when patients are unable to expectorate a specimen.The procedure uses sterile water or hypertonic saline to irritate the airway, increase secretions,promote coughing, and produce a specimen. It is also recommended for children as a preferredoption to gastric washings. 26 Sputum induction is classified as a high-risk procedure when performedon a person with suspected or known infectious TB. 26;229 There is a consensus in internationalbest practice guidelines that sputum induction should only be performed in an airborne isolationroom or if no such room is available a ventilated booth from which air is exhausted outside orHEPA filtered. 30;229 The committee agrees with this. These booths or local exhaust ventilation (LEV)systems must be maintained and regularly monitored to ensure they are working satisfactorily.• Aerosol-generating procedures such as the administration of medications by nebuliser onsuspected or confirmed cases of TB must be avoided in an open bay or in an unventilated areain all wards/departments. Treatment of an extrapulmonary TB open abscess or lesion whereaerosolisation of drainage fluid may occur should only be undertaken in an airborne isolationroom.Current international guidelinesThere are differing recommendations in the current international best practice guidelines on the typeof rooms suitable for patients with infectious TB. The CDC guidelines 229 recommend that all suspectedand confirmed TB cases be treated in negative pressure rooms while the NICE guidelines 26 advise a thatnegative pressure room is only required for suspected or confirmed MDR-TB cases. The NICE guidelinesfurther advise that while single rooms without specific ventilation systems can be used for non-MDR-TBpatients no immunosuppressed patients should be on the ward.Recommendation:Patients with known or suspected pulmonary or laryngeal TB should be admitted to anairborne isolation room (negative pressure isolation room with an ante room or a neutralpressure design as outlined in HBN 04 supplement 1). Hospitals need to have a riskassessment process to ensure the appropriate provision of isolation facilities (see figure 6.1).Availability of isolation roomsA study in 2003 reported that only 14% of Irish hospitals had an isolation room suitable for AirbornePrecautions. 237 While the available number of rooms may have increased with recent new builds andrefurbishments in Irish hospitals, it is likely that some hospitals have an insufficient number of isolationrooms with a ventilation system to isolate all known or suspected infectious TB cases.Hospitals should prioritise the building of airborne isolation rooms. New buildings or major renovations inacute general hospitals should have a minimum of one airborne isolation room to 150 beds or one to 75beds for regional/tertiary hospitals. Critical care and accident and emergency units should have at least oneairborne isolation room. 236-77-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRisk assessment for all confirmed or suspected pulmonary or laryngeal TB cases. 26Recommendation:All patients with suspected or known pulmonary or laryngeal TB must have a risk assessmentfor MDR-TB.Risk factors for MDR-TB include the following:• A history of prior TB treatment (especially incomplete treatment) and/or prior TB treatmentfailure• Contact with a known case of MDR-TB• Birth in a foreign country, particular a high incidence country for MDR-TB (Lithuania, Estonia,Latvia, Uzbekistan, Kazakhstan, China ( Henan & Liaoning provinces) Tomsk Oblast (RussianFederation) and Ecuador) (refer to www.who.int/tb/publications/mdr_surveillance/en/index.htmlfor latest information on countries with high incidence of MDR-TB)• HIV infectionRecommendation:Patients with suspected or confirmed MDR-TB must be admitted to an airborne isolation room(negative pressure isolation room with an ante room or a neutral pressure design as outlined inHBN 04 supplement 1). (This may require transferring the patient to another institution wherethe facilities, together with a physician experienced in the management of complex drugresistantcases are available).See figure 6.1 for risk assessment for patient placement if a sufficient number of airborne isolation roomsare not available.-78-

Figure 6.1Patient placement for Pulmonary or Laryngeal TB until a sufficient number of airborneisolation rooms (section 6.6) are available in all acute hospitals<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCFigure 6.1: Patient placement for pulmonary or laryngeal TB if a sufficient number of airborne isolationrooms (section 6.6) are not availableKnown or suspected infectious TB*YesKnown or suspected MDR-TB ¥YesNoAirborne isolation room (section 6.6) - rapidtest for rifampicin resistance. Considertransfer to another facility if none availableDoes ward have immunosuppressed † patients?YesNoAirborne isolation room (section6.6)If none available considertransfer to another ward/facilitySingle room*Definition of an infectious case> 10 years of ageCoughing, undergoing sputum inducing procedures, cavitations on CXR, sputum smear positive, suspected laryngeal involvement,extrapulmonary TB in an abscess or lesion if aerosolisation of drainage fluid occurs. Bal AFB positive if any of the following ispresent: Cavitations on CXR, suspected or confirmed MDR-TB, admitted to a ward or living with immunosuppressed individuals.< 10 years of ageCavitations on CXR, sputum smear positive (not BAL or gastric washings) suspected laryngeal involvement, extensive pulmonaryinfection, congenital TB & undergoing procedures involving oropharyngeal airway, extrapulmonary TB in an abscess or lesion ifaerosolisation of drainage fluid occurs.¥Risk factors for MDR-TBA history of prior TB treatment (especially incomplete treatment) and/or prior TB treatment failure.Contact with a known case. Birth in a foreign country, particular a high incidence country for MDR-TB (Lithuania, Estonia, Latvia,Uzbekistan, Kazakhstan, China (Henan & Liaoning provinces) Tomsk Oblast (Russian Federation) & Ecuador) (refer towww.int/tb/publications/mdr_surveillance/en/index.html for latest information on countries with high incidence of MDR-TB).†Immunosuppressed is defined as either due to disease or therapies e.g. HIV, individuals receiving >15mg prednisone or equivalentfor more than four week or other immunosuppressive agents for cancer, chemotherapeutic agents, anti-rejection drugs for organtransplantation and TNF-α antagonists or as defined by the attending consultant.Patients with HIVA HIV positive patient with suspected or confirmed pulmonary or laryngeal TB must be placed in anairborne isolation room. HIV positive or other immunosuppressed individuals should not be exposedto possible or confirmed infectious TB cases. In wards with HIV positive patients all aerosol-producingprocedures (e.g. sputum induction) regardless of whether a diagnosis of TB has been considered or notshould be conducted in airborne isolation rooms. 26-79-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCEmergency departmentsEmergency departments (ED) without airborne isolation rooms must have a process in place to prioritisetransfer of suspected or confirmed pulmonary or laryngeal TB cases to an appropriate room. ED with nosingle or isolation rooms should place a surgical mask on the patient and place him/her in an examinationroom while awaiting transfer. This room should be left vacant for at least one hour after the patient istransferred to allow for a full exchange of air. 230Bronchoscopy departmentsBronchoscopy should preferably be performed in an appropriate negative pressure suite with adequateventilation. Unnecessary staff and other patients should be excluded during the procedure. If endoscopyrooms are without air handling equipment, a bronchoscopy procedure on a patient with suspected orconfirmed laryngeal or pulmonary TB should be undertaken at the end of the list for the day, or in thepatient’s room. Avoid placement of recovering patients in a multi-bedded ward. Bronchoscopy for otherclinical reasons on a confirmed TB case should be delayed if possible until the patient has had threesputum smear negative samples.AutopsyIt has been estimated that the risk of TB in mortuary workers is 100-200 times more than the generalpopulation. 238 Recommendations to reduce the risk of infection are detailed in good practice guidelinesfrom the Royal College of Pathology, 2003. 239LaboratorySee chapter 4 for infection control precautions in the laboratory.Use of personal protective equipmentIn addition to the use of personal protective equipment (PPE) as outlined in Standard Precautions (seeappendix 10), respiratory protection is advised for HCWs when Airborne Precautions are applied.Health care workersExposure of HCWs to TB should be minimised by reducing the number involved in the direct care of aninfectious case. Recommendations for the use of respiratory protective equipment vary from country tocountry. The NICE guidelines 26 recommend that healthcare staff do not need to use respiratory protectionunless MDR-TB is suspected or for cough-inducing procedures such as bronchoscopy and sputuminduction. Where MDR-TB is suspected or known they recommend that staff and visitors use FFP3 masksor equivalent. The NICE guidelines also recommend that patients while infectious should wear a surgicalmask when they are outside their room, for example visiting the X-ray department. In New Zealand andCanada, N95 (equivalent to European FFP2) masks are recommended when caring for patients with knownor suspected infectious pulmonary TB. 30;52 In the USA, the N95 mask is recommended as the minimumstandard for respiratory protection in areas where patients with suspected or confirmed infectious TBmight be encountered. A higher level of protection should be considered where the risk for exposure to M.tuberculosis is especially high e.g. cough inducing procedures. 230Respiratory masks are only effective if there is a tight seal to the wearer’s face. Fit testing is a method forchecking that the mask matches the person’s facial features and seals adequately to the wearer’s face.A good seal is only possible when the wearer is clean shaven. Fit testing will also help to ensure thatincorrectly fitting respiratory masks are not selected for use. 240A respiratory protection programme for staff advised to wear respiratory masks should be provided byeach healthcare facility to ensure compliance with the following health and safety legislation and standard:• Safety, Health and Welfare at Work Act, 2005• Safety, Health and Welfare at Work (General Application) Regulations 2007 (S.I. No. 299 of 2007).Chapter 3 of Part 2: Personal Protective Equipment• Safety, Health and Welfare at Work (Biological Agents) Regulations 1994 (S.I. No. 146 of 1994) (asamended by S.I. 248 of 1998)• IS EN 529:2005 (Irish Standard on Respiratory Protective Devices).-80-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCThe respiratory protection programme should include the following;Governance• Identify department responsible to deliver the respiratory protection programme• Identify personnel responsible for the implementation of the respiratory protection programme• Allocation of resources to deliver the programme• Selection, purchase and supply of suitable masks to each healthcare facility• Storage of equipment• Maintenance of equipment• Disposal of used equipment• Record keeping.Theoretical information, training and instruction including:• Types of risk• Knowledge and understanding of respiratory equipment including limitations• Personal factors including medical conditions, improper fitting• Fit testing and fit checking.Practical training• An initial fit test using qualitative method• Ongoing check fitting to confirm the seal each time the mask is donned• Donning, removing and disposing of masks.FFP2 or FFP3 respiratory masks are unsuitable for HCWs with facial hair as it affects the seal between themask and the face. Beards, sideburns or even a visible growth of stubble will affect the face seal of suchmasks which rely on close contact between the face and the mask.For HCWs where the removal of facial hair is not possible, an employer must look at the provision ofsuitable respiratory equipment which does not rely on a good face seal for protection e.g. powered/airsuppliedhoods. Otherwise, redeployment may be required as an employer cannot ensure the safety ofpersonnel.-81-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendation:A respiratory protection programme for staff advised to wear respiratory masks should beprovided by each healthcare facility.HCWs (including HCWs visiting a patient in their own home) should wear FFP2 masks whencaring for patients with suspected or confirmed infectious TB where MDR-TB or XDR-TB is notsuspected. These patients are usually non-infectious after a minimum of two weeks treatment.The supervising clinician should be consulted before the use of masks is discontinued (section6.7).HCWs should wear FFP3 masks when undertaking cough-inducing procedures on all patients(fully susceptible and resistant strains included) e.g. sputum induction, bronchoscopy,administration of aerosolised medications, airway suctioning, endotracheal intubation, caringfor patients on mechanical ventilation and during treatment of lesions/abscesses whenaerosolisation of drainage fluid is anticipated.HCWs (including HCWs visiting a patient in their own home) should wear FFP3 maskswhen caring for patients with suspected or confirmed infectious MDR-TB or XDR-TB. Thesupervising clinician should be consulted before the use of masks is discontinued (section 6.7).A respiratory protection programme should be provided for all HCWs who may be requiredto use respiratory masks during the course of their work. HCWs should be fit tested by atrained professional as part of this programme. All HCWs should fit check each time a mask isdonned.PatientsCDC and NICE guidelines advise that patients with suspected TB when not in an isolation room should wearsurgical masks to reduce the expulsion of droplet nuclei into the air. Respirators masks (FFP2/3) are designedto filter the air before it is inhaled by the person wearing the mask. In addition, correctly wearing respiratorymasks increases respiratory effort which can be difficult for a patient already compromised. In line with this,the recommendation of the National TB Advisory Committee is as follows:Recommendation:Patients should wear a surgical mask while they are infectious, when they are outside theirroom, for example visiting the X-ray/OPD department.Removal of PPERemove PPE in the following sequence:1. Gloves2. Apron/gown3. Decontaminate hands4. Eye wear5. Respiratory mask – (handle with the straps of the mask to avoid touching the front)6. Decontaminate hands.Gloves, apron/gown are removed in the room. Mask and eyewear are removed outside the room.-82-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCIn addition:• Discard PPE that is contaminated with blood or body fluids from patients with known orsuspected infection in healthcare risk waste• Discard respiratory masks in healthcare risk waste• Gloves, aprons/gowns and eye wear are not required for Airborne Precautions but are requiredto be worn if contact with blood or body fluid is anticipated as per Standard Precautions(appendix 10).Patient transportationLimit the movement and transport of the patient to essential purposes only. If transport or movement isnecessary, staff should ensure that precautions are maintained to minimise the risk of transmission to otherpatients and the contamination of environmental surfaces or equipment.Transfer of patients with suspected or confirmed infectious TBInternational best practice guidance on respiratory protection required for HCWs when transferring apatient with suspected or confirmed TB is not consistent. Guidance from the Public Health Agency ofCanada and the Bureau of TB control in New York recommend that HCWs wear the equivalent of FFP2masks during transfer. 30 77 CDC recommends that FFP2 or equivalent masks are only required for transferif the patient is unable or unwilling to wear a surgical mask. 230 The newly published Scottish guidelines donot specifically address transfer however, do advise the use of FFP3 masks if intensive nursing is requiredleading to close contact (equivalent to household contact) for a cumulative total of eight hours or more. 241The following actions are recommended prior to patient transfer:• The transferring facility should inform transport personnel (emergency medical technicians,porters) and the receiving department/facility of the need for Airborne Precautions• Prior to accepting a patient with known or suspected TB, it is the responsibility of the receivingfacility to ensure compliance with facilities as described above under patient placement• Remove contaminated apron/gown/gloves (if worn) and mask and dispose prior to transportingpatients. Staff do not need to wear FFP2/FFP3 mask during internal hospital transportationunless the patient is unable to wear a surgical mask (e.g. confused, respiratory distress)• Ambulance staff should consider the use of FFP2 or FFP3 mask in the following situations: (a) thepatient is unable or unwilling to wear a surgical mask; (b) it is anticipated that the duration of thejourney will be ≥ 8 hours (≥ 4 hours if HCW is immunocompromised) and (c) if the patient haseither MDR-or XDR-TB (consult infection prevention and control team in this situation)• Request the patient to wear a surgical mask which should be changed when heavilycontaminated and/or wet or if torn. Educate on cough etiquette and ensure patient has a supplyof tissues• Don FFP2 or FFP3 mask prior to handling the patient at the transport destination (e.g. X-ray,bronchoscopy suite)• Transport equipment (stretcher, bed, wheelchair) used to transport the patient should becleaned and disinfected using a disinfectant with 1,000ppm of available chlorine if contaminatedwith sputum/respiratory secretions.Patients and visitorsTo preserve privacy and confidentiality, restricting visiting to immediate family should be discussed with thepatient.Each hospital should have a system in place to alert visitors to check with ward nursing staff regarding handhygiene and other requirements before and after visiting a patient with TB.Patients with TB and their visitors/carers should be given information on the following;• Preventing transmission of TB• Medications used to treat TB and the importance of compliance with the treatment plan• The range and need for appropriate infection prevention and control precautions• Hand hygiene• How to don/remove masks.-83-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC6.6 Discontinuation of Airborne PrecautionsDiscontinue Airborne Precautions, if MDR-TB is not suspected or confirmed, when all of the criteria (1-3)below are met: 26;771. On standard multi-drug therapy for a minimum of two weeks2. Clinical symptoms are improving3. Three consecutive (properly performed) negative sputum smear examinations collected over 48to 72 hours of which at least one should be an early morning sample. Patients unable to producesputum i.e. no productive cough should be discussed with clinical and infection prevention andcontrol teams.See figure 6.2 for criteria for discharge from hospital.Patients who are on standard multidrug therapy for TB and remain hospitalised after Airborne Precautionshave been discontinued should have sputum tested for AFB smear every one to two weeks. 77Discontinue Airborne Precautions for suspected or confirmed MDR-TB when all of the following criteria(1-3) are met: 301. Three consecutive sputum samples are smear and culture negative after six weeks incubation2. Current treatment with anti-TB regimen to which the strain is known or likely to be susceptible3. Clinical symptoms are improving/resolving.See figure 6.2 for criteria for discharge from hospital.Discontinue Airborne Precautions for suspected or confirmed XDR-TB when:• Patients with XDR-TB should remain in airborne isolation for the duration of their hospital stay. 30Such patients should not be discharged to home until three consecutive sputum samples aresmear and culture negative after six weeks incubation.Discontinue Airborne Precautions for suspected cases when TB is ruled out if:• Three sputum samples are negative for AFB taken on separate days or an alternative diagnosis ismade that accounts for respiratory symptoms (e.g. cancer, pneumonia).If no alternative diagnosis is made such patients should not be admitted to an open ward withimmunosuppressed patients until culture negative confirmed.6.7 Discharging Patients with TB from HospitalMDR-TB not suspected or confirmedPatients who are confirmed with infectious TB (but MDR-TB is not suspected or confirmed) can bedischarged home in most situations from hospital while still sputum AFB positive when the followingcriteria are met:1. Commenced on standard multidrug anti-TB therapy2. Clinical symptoms are improving3. Can be discharged to a stable residence at a verified address4. Is willing and able to observe risk reduction activities e.g. respiratory hygiene, cough etiquetteand follow discharge instructions (see appendix 11)5. Is willing and able to follow up with DOT if necessary (see appendix 9 for HSE South (Cork andKerry) DOT referral form)6. Arrangements are in place for outpatient clinic review.These patients should not be discharged to following situations unless they fulfill criteria 7 and 8below in addition to criteria 1 to 6 above:• Congregate setting (nursing or care home, prison, etc.)• Living with immunosuppressed* 2 individuals2*Immunosuppressed is defined as either due to disease or therapies e.g. HIV, individuals receiving >15mg prednisone or equivalentfor more than four week or other immunosuppressive agents for cancer, chemotherapeutic agents, anti-rejection drugs for organtransplantation and TNF-α antagonists or as defined by the attending consultant.-84-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• Living with children < five years of age who have not been evaluated by a public health physicianfor window period prophylaxis for LTBI• Settings where the patient or a family member requires care from HCWs (home helps, nursingstaff) for several hours a day7. Completed at least two weeks of standard multi drug anti-TB treatment8. Three consecutive sputum AFB negative samples taken at least 24 hours apart with at least oneearly morning specimen (if patient cannot produce sputum i.e. non-productive cough discuss withclinical, public health and infection prevention and control teams). 77MDR-TB suspected or confirmedPatients who are confirmed or suspected with infectious MDR-TB should not be discharged home in mostsituations unless the following criteria (1-7) are met:1. Clinical symptoms are improving2. Current treatment with anti-TB regimen to which the strain is known or likely to be susceptible3. Three consecutive sputum AFB negative samples taken at least 24 hours apart with at least onesample an early morning specimen (if patient cannot produce sputum i.e. no productive cough,discuss with clinical and infection prevention and control teams)4. Can be discharged to a stable residence at a verified address5. Is willing and able to observe risk reduction activities e.g. respiratory hygiene, cough etiquetteand follow discharge instructions (see appendix 11)6. Willing and able to follow up with DOT (see appendix 9)7. Arrangements are in place for outpatient clinic review.These patients should not be discharged to the following situations unless they fulfil criterion 8 belowin addition to criteria 1-7 above:• Congregate setting (hostel, nursing or care home, prison, etc.)• Living with immunosuppressed individuals• Living with children < five years of age who have not been evaluated by a public health physicianfor window period prophylaxis for LTBI• Settings where the patient or a family member requires care from health care workers (homehelp, nursing staff) for several hours a day 778. Three consecutive sputum samples are smear and culture negative after six weeks incubation.If patient cannot produce sputum i.e. does not have a productive cough, discuss with clinical,public health and infection prevention and control teams 30-85-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCFigure 6.2: Criteria for discharging patients with suspected or confirmed infectious TB from a hospitalTreatment with anti-TBregime commenced to whichorganisms are known or likelyto be susceptibleYesAssess if patient can be treated as outpatientYesPatient is medically and mentallystable, has clinically improved(even if sputum AFB positive)and is ready for dischargeNoContinueinpatient careDoes the patient meet ALL of the following8 criteria?1. Can be discharged to a stable residenceat a verified address2. Will NOT be discharged to a congregatesetting such as a shelter, nursing home,hostel, prison, etc3. Will not have significant contact or livewith immunosuppressed* individuals4. Patient or a family member in the homewill not need attendant or visiting nursingservices for several hours a day5. Is willing and able to observe riskreduction activities e.g. respiratoryhygiene, cough etiquette and followdischarge plan (see appendix 11)6. Willing and able to follow up with DOT ifnecessary7. If there are children < five years at homea plan for evaluation by public healthdepartment must be in place for windowprophylaxis for LTBI8. MDR-TB not suspected or confirmedYesEducate patient aboutdischarge plan and outpatienttreatmentSee appendix 11 fordischarge instructionsEnsure that1. OPD appointment ismade2. DOT referral form (seeappendix 9) is sent topublic health nursingdepartment if required3. Discharge letter to GP iscompletedDischarge from hospitalSee section 6.7 for discharge criteria for patientsnot meeting 1-8 aboveAdapted with kind permission from Tuberculosis, Clinical Policies and Protocols. New York City Department of Health and MentalHygiene (2008). Available from www.nyc.gov/html/doh/downloads/pdf/tb/tb-protocol.pdf.6.8 EducationHealthcare workersThere should be an ongoing education programme for HCWs that includes the following:• Signs and symptoms of TB• Definition of infectious TB• Local guidelines and protocols for the management of TB• Local incidence of TB• Management of dual action, negative pressure ventilated rooms or neutral pressure designrooms*Immunosuppressed is defined as either due to disease or therapies e.g. HIV, individuals receiving >15mg prednisone or equivalentfor more than four week or other immunosuppressive agents for cancer, chemotherapeutic agents, anti-rejection drugs for organtransplantation and TNF-α antagonists or as defined by the attending consultant.-86-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• Management of sputum induction to minimise risk to staff and other patients• Reducing risk associated with immunosuppressed patients.Education of patients/family/carersSee appendices 6 and 11 for patient information leaflet and hospital discharge leaflet. Some patients whoare infectious can remain at home in the household that has already been exposed, as it has been shownthat the risk of additional transmission of infection in this setting is extremely low. 52The infectious patient must be instructed to take the following precautions until advised by their doctor toreturn to normal activities:• Stay at home and not go to work, school, public places or any other locations where there willbe previously unexposed people until advised to do so by the treating clinician• No visits by previously unexposed people• No visits by children (young children living at home will be assessed by public health doctorsregarding the need for LTBI window prophylaxis)• Avoid visits by relatives or friends who are immunosuppressed• Cover their mouth and nose with a tissue when sneezing or coughing.The infectious patient must be educated regarding:• Safe disposal of tissues and the importance of hand washing after coughing/sneezing• Disease transmission and disease control• The importance of compliance with medication• Side-effects of anti-TB medication• Contact tracing.-87-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC7. BCG VaccinationThe Bacillus Calmette-Guerin (BCG) vaccine was derived by in-vitro attenuation of the bovine tuberclebacillus between the years 1908 and 1918 in France. WHO encouraged widespread use of the vaccinestarting in the 1950s and as a result more than 70% of the world’s children now receive BCG. However,the policies on BCG vaccination differ greatly both nationally and internationally, reflecting differences ofexpert opinion as to the mechanism of action and effectiveness of the vaccine. 242 The potential loss of thetuberculin test as an indicator of natural infection with tubercle bacilli when BCG is routinely used may be adisadvantage that has to be weighed against the benefits of the vaccine.7.1 Clinical EfficacyThe clinical efficacy of a vaccine is measured in terms of the percentage reduction in disease amongvaccinated individuals that is attributed to vaccination i.e. the proportion of those vaccinated who gainprotective immunity from the vaccine. 243 BCG vaccines are generally given to protect against TB. BCGvaccine does not give 100% protection but it does protect against the more serious forms of the disease,e.g. TB meningitis especially in the young. The NICE guidelines cite evidence from both randomisedcontrolled trials and case control studies for the efficacy of BCG vaccination in infancy in preventingpulmonary TB infection, TB deaths, TB meningitis, laboratory-confirmed TB cases and disseminated TB. 26BCG vaccine is probably most consistently effective against tuberculous meningitis and miliary TB withprotection lasting approximately 15 years. It is universally agreed that BCG vaccine protects small childrenfrom severe forms of childhood TB especially in areas with a high risk of infection. 244;245 In such areas withhigh infection risk, WHO EPI programme reports a global coverage of BCG in children less than one yearat around 85%. 246An extensive study by Tala et al. attempted to interpret variations in the efficacy of BCG vaccine. Factorsconsidered to be important are age at administration, prior exposure to environmental non-tuberculousmycobacteria, efficacy of BCG vaccine including vaccine quality, host genetics and nutrition, infectionincidence, the study design and the route of administration. 247 A meta-analysis of large numbers of BCGefficacy trials revealed a protection rate against pulmonary TB of 86% in randomised trials and 75% in casecontrol studies despite extensive use of the vaccine. 40 Colditz et al. in a meta-analysis estimated the overallefficacy of BCG in preventing pulmonary TB to be approximately 50%. Against TB meningitis the efficacywas 64% and against TB deaths 71%. 248 In summary, there is overall agreement that the efficacy of BCGis at its best about 80% 249 and of 15-20 years duration. 250 Kritski et al. reported a protection rate of 69%against MDR-TB in a recent study in 1996. 2517.2 Criteria for Discontinuation of a Universal BCG Vaccination ProgrammeIn 1994, the International Union against Tuberculosis and Lung Disease (IUATLD) expert group publishedcriteria for discontinuing BCG vaccination programmes in countries with a low prevalence of TB. 252 Thesecriteria are outlined as follows:1IUATLD criteriaBefore consideration is given to whether a country stops or modifies its BCG programme, the followingrequirements must be met:• There is a well functioning TB control programme• There has been a reliable reporting system over the previous five or more years, enabling theestimation of the annual incidence of active TB by age and risk groups, with particular emphasison TB meningitis and sputum smear positive pulmonary TB. In Ireland, national data enabling adetailed epidemiological analysis for the country, as a whole was first produced by HPSC in the1998 National TB Report. The 2006 National TB Report is the ninth national TB report.• Due consideration has been given to the possibility of an increase in the incidence of TB resultingfrom the epidemiological situation of AIDS in that country.15With one of the following• The average annual notification rate of sputum smear positive pulmonary TB should be 5 per100,000 or less during the previous three years-88-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCor• The average annual notification rate of TB meningitis in children under five years of age should beless than one case per ten million general population over the previous five yearsor• The average annual risk of TB infection should be 0.1% or less. This is not applicable to Ireland.The national rate for sputum smear positive pulmonary TB has been under 5 per 100,000 for the threeyears prior to 2006. In 2005 the rate was 3.3 per 100,000, while in 2004, 2003 and 2002, the rates were3.5 per 100,000, 3.7 per 100,000 and 3.1 per 100,000 respectively. However, data from between 2001 and2006 indicate that there were four cases of TB meningitis notified in children aged less than five years, ofwhom two were culture positive and three had not received BCG vaccine. 20When considering the importance of neonatal BCG vaccination, it is worth considering the practice inother European countries. For example, Sweden discontinued routine neonatal BCG vaccination in 1975when they had a total notification rate of 20 per 100,000 population and an age-specific incidence ratefor children aged 0-14 years of 0.3 per 100,000. While the national crude rate in Ireland is less than 20 per100,000 population, the 2006 age-specific incidence rate for children 0-14 years was 2.4 per 100,000, eighttimes the rate recorded in Sweden when they discontinued neonatal BCG vaccination. In 2005, 2004, 2003,2002, 2001 and 2000, the age-specific incidence rate for children aged 0-14 years was 3.0 per 100,000,1.2 per 100,000, 2.9 per 100,000, 2.2 per 100,000, 1.9 per 100,000 and 1.9 per 100,000 respectively. In1999, the age-specific incidence rate for children aged 0-14 years was 5.1 per 100,000 population, almostseventeen times the rate recorded in Sweden. In 1998, the corresponding figure was 3.5 per 100,000population almost twelve times the rate recorded in Sweden when they discontinued BCG. 20It is also notable that Finland who moved from a universal newborn BCG vaccination programme to atargeted risk group programme in September 2006 had only five notified cases of TB in the 0-2 year oldsbetween 1997 and 2001 and no cases of TB meningitis in the 0-14 year olds notified in this period. Since1970, only two cases of TB meningitis have been notified nationally in Finland. The national incidencerate for TB is 11 per 100,000 and 65% of cases occur in those aged over 60 years. Foreign-born patientsrepresent 6 to 9% of the total. 253When Canada discontinued universal BCG in 2002, the national TB notification rate was 5.2 per 100,000and the notification rate was 1.6 per 100,000 in 0-14 year olds. 254Also, rates of TB notifications in 1998 in the following Nordic countries that have discontinued neonatalBCG programmes are much lower than in Ireland and among the best in the world as outlined below:• Sweden = 5.0 per 100,000• Norway = 5.0 per 100,000• Denmark = 9.6 per 100,000• Iceland = 5.8 per 100,000.As well as the IUATLD criteria, there are additional considerations which should also be reviewed whendeciding to modify or stop a universal BCG programme as outlined below:• Costs• Adverse reactions to BCG• Risk groups: In the event of discontinuation of the BCG vaccination programme for the generalpopulation, it may be advisable to continue it in certain well-defined population groups with aknown high notification rate of active TB. 253While Ireland meets the IUATLD criteria on the basis of overall smear positive pulmonary TB reportingrates, the number of TB meningitis cases in children and general rates of TB in children remain a concern.Also, the TB control programme is currently under review and it is likely that recommendations will bemade for strengthening the programme. In light of these findings, the continuation of the universalprogramme of neonatal BCG vaccination is recommended in Ireland at this time.-89-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendation:The continuation of a universal programme of neonatal BCG vaccination is recommended inIreland at this time.7.3 Dose and Route of AdministrationBCG Vaccine Statens Serum Institut (SSI) is the only available licensed BCG vaccine in Ireland. It containsthe Danish strain 1331. It does not contain thiomersal or any other preservatives. It may be givenconcurrently with another live vaccine, but if they are not given at the same time an interval of at least fourweeks should be allowed between such vaccines. It can also be given at the same time as killed vaccinese.g. DTaP/IPV/Hib/Hepatitis B, PCV (pneumococcal conjugate vaccine) or Men C.Recommendation:When BCG is given to infants there is no need to delay the primary immunisations. No furtherimmunisation should be given in the arm used for BCG immunisation for at least three monthsbecause of the risk of regional lymphadenitis.Infants under 12 months of ageThe recommended dose is 0.05ml by intradermal injection of the reconstituted vaccine at one site over themiddle of the deltoid muscle.Adults and children 12 months and overThe recommended dose is 0.1ml by intradermal injection of the reconstituted vaccine and given at onesite over the middle of the deltoid muscle.Although the protection afforded by BCG vaccine may wane with time, there is no evidence that repeatvaccination offers significant protection and repeat BCG is not recommended. If re-immunisation with BCGis being considered expert advice should be sought.Detailed instructions including illustrations are available from the Immunisation <strong>Guidelines</strong> for Irelandprepared by the National Immunisation Advisory Committee. 2557.4 Indications for BCG VaccineRecommendation:Training for health professionals in the correct administration of BCG vaccine is recommended.Those administering vaccine should be aware of indications, contraindications, immunisationand adverse reactions associated with BCG.Groups in whom BCG vaccine is indicated:1. Newborn babies2. Unvaccinated children aged one to 15 years (i.e. those with no documented evidence of BCG orwithout a characteristic scar)i. Children aged three months to less than six years who are not in an at-risk environment5F1∏ do1 ∏ Children in at-risk environments include those who are contacts of a pulmonary TB case, who are from an area of high endemnicity(annual TB rates of ≥ 40/100,000) or whose parents are from an area of high endemnicity or who have household contacts who belongto an at-risk group for TB-90-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC℘not need a TST (Mantoux test) prior to receiving BCG vaccine6F 2256ii. Childr en in at-risk environments should have a TST (Mantoux test) prior to BCG.3. Unvaccinated (that is without adequate documentation or a characteristic scar) Mantoux negativeimmigrants under 16 years of age who were born or who have lived for a prolonged period (atleast three months) in a high incidence country7F3♦ OR aged 16-35 years from a sub-Saharan Africancountry or country with a TB incidence of 500 per 100,000 264. Unvaccinated Mantoux negative contacts aged 35 years and under of cases with active pulmonaryTB. Children under five years of age in contact with smear positive TB should be referred to acontact tracing clinic for investigation and then immunised with BCG as indicated.5. Members of special at-risk groups such as the travelling community due to the logistical difficultiesof providing alternative control measures and follow up of contacts6. Unvaccinated Mantoux negative persons under 16 years of age intending to live or work with localpeople in high incidence countries for more than one month 2577. BCG is indicated for unvaccinated healthcare workers (HCWs) aged

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC7.6 InteractionsAdministration of blood or plasma transfusions, hepatitis B vaccine, hepatitis B immunoglobulin and normalimmunoglobulin are thought not to reduce the effectiveness of BCG vaccine. 258-261 A baby who has receivedblood or plasma transfusions can be subsequently immunised with BCG, after the observation period(24 hours) for transfusion reactions has ended. A baby who has received hepatitis B vaccine, hepatitis Bimmunoglobulin or normal human immunoglobulin can be subsequently immunised with BCG withoutdelay.7.7 Administration of BCG VaccinationDetailed instructions are available in chapter 2 of the Immunisation <strong>Guidelines</strong> for Ireland available atwww.immunisation.ie and also on the Staten Serum Institut (Denmark) website atwww.ssi.dk/sw4145.asp.7.8 Immunisation Reaction and Care of the Immunisation SiteThe expected reaction to a successful BCG vaccination seen in 90-95% of recipients is induration at theinjection site followed by a local lesion which starts as a papule two or more weeks after vaccination. It mayulcerate and then slowly subside over several weeks or months to heal leaving a small flat scar. It may alsoinclude enlargement of a regional lymph node to less than 1cm.It is not necessary to protect the site from becoming wet during washing and bathing. The ulcer shouldbe encouraged to dry and abrasion (for example by tight clothes) avoided. Should any oozing occur atemporary dry dressing may be used until a scab forms. It is essential that air is not excluded. If absolutelynecessary (e.g. to allow swimming), an impervious dressing may be applied but only for a short period as itmay delay healing and cause a larger scar.Further observation after routine vaccination with BCG is not necessary, other than as part of monitoring ofthe quality of the programme, nor is further tuberculin testing recommended.Severe injection site reactions, large discharging ulcers, abscesses and keloid scarring are most commonlycaused by faulty injection technique, excessive dosage or vaccinating individuals who are tuberculinpositive. It is essential that all healthcare professionals be properly trained in all aspects of the processinvolved in tuberculin skin tests and BCG vaccination.7.9 Adverse ReactionsLocal: Side effects include local induration, pain and occasionally ulceration, enlargement of a regionallymph node greater than 1cm, abscess formation, lupoid reaction and inflammatory and suppurativeadenitis. 109General: Headache, fever and generalised lymphadenopathy can rarely occur (in less than one in 1,500vaccinated). Anaphylactic reaction and disseminated BCG complications (such as osteitis, osteomyelitis ordisseminated BCG infection) are also very rare. Disseminated BCG infection occurs in approximately twoper one million persons, primarily in persons with severely impaired immune systems. 1091Management of adverse reactionsLocal adverse reactions to BCG vaccine occur in 1-2% of immunisations. Severe local reactions (ulcerationgreater than 10mm, caseous lesions, abscesses or drainage at the injection site) or regional suppurativelymphadenitis with draining sinuses following BCG vaccination should be discussed with a respiratoryphysician or consultant paediatrician. 255Most experts do not recommend treatment of draining skin lesions or chronic suppurative lymphadenitiscaused by BCG vaccine because spontaneous resolution occurs in most cases. Large needle aspiration ofsuppurative lymph nodes may hasten resolution. There is little evidence to support the use of either locallyinstilled anti-mycobacterial agents or systemic treatment of patients with severe persistent lesions.-92-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCDisseminated BCG infection should be referred to a respiratory or infectious disease consultant forspecialist advice and will normally require systemic anti-tuberculous treatment and mandate a detailedimmunological investigation. 2557.10 Tuberculin Testing prior to BCG ImmunisationBCG vaccine should not be administered to an individual with a positive tuberculin test. Those withstrongly positive tests should be referred to a respiratory or infectious disease physician for assessment ofthe need for further investigation and treatment.A TST (Mantoux test) is necessary prior to BCG vaccination for:∏1. Children aged three months to aged under six years in at-risk environments8F 42. Persons aged six years and older3. Infants and children under six years of age with a history of ever having lived or had a prolongedstay (more than one month) in a country of high endemnicity (i.e. an annual TB rate of ≥40/100,000)4. Those who have had close contact with a person with known TB and5. There is a history of TB in a household contact in the last five years.BCG can be given up to three months following a negative tuberculin test.The standard skin test for use in Ireland is the Mantoux 2TU/0.1ml tuberculin PPD (see chapter 2).Recommendation:BCG should not be administered to an individual with a positive tuberculin (or IGRA) test.For further detail on BCG, see the Immunisation <strong>Guidelines</strong> for Ireland available at www.immunisation.ie4 ∏ Children in at-risk environments include those who are contacts of a pulmonary TB case, who are from an area of high endemnicity(annual TB rate ≥ 40/100,000) or whose parents are from an area of high endemnicity or who have household contacts who belong toan at-risk group for TB.-93-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC8. Contact TracingContact tracing is a systematic process with three main objectives:• To identify and initiate treatment of secondary cases• To identify TB infected contacts in order to offer treatment for LTBI• To identify those not infected for whom BCG vaccination may be appropriate.Contact tracing may also be undertaken to find a source of infection or any co-primary cases where there isevidence of recent infection, as indicated by infection in children.Current Irish epidemiological data indicate that between 6 and 10% of TB cases are diagnosed bycontact tracing. 19;20;262 UK studies from the 1990s have shown that up to 10% of TB cases are diagnosedby contact tracing, that disease is detectable in about 1% of all screened contacts, 263-270 and is normallyfound in non-BCG vaccinated close contacts of pulmonary smear positive cases during the initial round ofinvestigation. 263-267Early case detection as a result of contact tracing reduces the period in which cases are infectious andthe risk of infection being transmitted to others. Evaluation of highest risk contacts can infer recenttransmission if infection or disease is detected. Evidence of recent infection supports the extension of thecontact investigation to progressively lower-risk contacts. Screening should be concluded when levels ofinfection detected in the tiers of at risk contacts equate to those in the general community.Recommendation:Contact tracing should be conducted according to the concentric circle approach, 271 wherebycontacts with greatest exposure to the index case are prioritised for screening.8.1 Factors Predicting TB TransmissionTB is spread by airborne droplet nuclei (approximately 1 to 5 microns in diameter, containing 1 to 10 bacilli)which are released in an aerosol from an individual with infected pulmonary sites when they cough, sneezeor sing. Sociability of the index patient may contribute to disease transmission because of the increasednumber of contacts and the intensity of exposure. 51 The amount of contact necessary for TB infection tobe transmitted is variable. It depends on the infectiousness of the source case, the susceptibility of theperson in contact with the case and the environment in which contact occurs. Factors that predict likelytransmission of TB are outlined below and it is important to consider all these factors together whenevaluating the infectiousness of a case. 272Infectiousness of the source caseAnatomical site of diseaseCases with TB in pulmonary and laryngeal sites primarily transmit infection. 273;274 In such cases, determiningwhether or not AFB are present on microscopic examination of sputum is an important factor inestablishing infectiousness. Infectious pulmonary and laryngeal cases should be considered a priority forcontact investigation.Cases of extrapulmonary TB are typically non-infectious and contact investigations should be aimed atidentifying a source of infection in those with greatest exposure to the case (especially where there isevidence of recent infection e.g. TB in a child). This is especially important if the case appears to haveresulted from recent transmission e.g. meningeal TB in a child. Diseased tissues are not usual infectionsources, although aerosol-producing procedures (e.g. autopsy, embalming and irrigation of a drainingabscess) undertaken without infection control precautions are considered an infection risk. 227;275-278156BSputum bacteriologyA case of TB whose sputum is smear positive, defined as a patient with minimum of one sputum specimen-94-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCpositive for AFB9 by microscopy is thought to be six to 10 times more contagious than a smear negativecase, while laryngeal TB cases are four to five times more contagious than smear positive pulmonarycases. 30;279Table 8.1: Definition of an infectious TB caseInfectious TB case• Sputum smear positive pulmonary TB• Laryngeal TBTB case presumed infectiousfor contact tracing purposes• BAL positive: (see below)The relative infectiousness of positive bronchial washings or BAL is unknown but some consider suchspecimens equivalent to sputum. 280 The US approach is to consider all BAL positive patients as infectious asthose who are sputum smear positive 51 (table 8.1). It is recommended that a precautionary approach shouldbe taken with BAL smear positive cases.Recommendation:• Infectious pulmonary and laryngeal cases are priorities for contact investigation. Aprecautionary approach should be taken with BAL smear positive cases• Those BAL smear positive cases with cavitation on chest X-ray, MDR-TB or XDR-TB or wherecontacts are immunosuppressed or are under 5 years of age should be presumed infectiousfor contact tracing purposes• The determination of infectivity of all other BAL smear positive patients should beconsidered on a case-by-case basis (clinical/microbiology/public health input).Radiographic findingsPatients who have lung cavities observed on a chest radiograph typically are more infectious than thosewith non-cavitary disease. 278;281;282 This is an independent predictor after bacteriological findings are takeninto account.AgeChildren younger than 10 years of age with pulmonary TB are rarely contagious because their pulmonarylesions are small (paucibacillary disease), cough is not productive, and few or no bacilli are expulsed. 109Generally, contact tracing investigations involving young children should be geared towards identifyingthe source and co-primary cases. However, although unusual, transmission from young children has beenrecorded. 283;284Recommendation:Young children under 10 years of age with pulmonary disease are rarely infectious. Suchcontact tracing investigations should be focused on finding a source and co-primary cases.Susceptibility of ContactsAgeChildren under five years of age are more likely to develop disease following recent infection. 110 Theincubation period is usually short, and severe forms of TB are common. Children under five years of ageshould be assigned a high priority for contact investigation.-95-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCImmunosuppressionImmunosuppressed individuals should be assigned a high priority for contact investigation. TB patientswho are HIV-infected with low CD4 T-cell counts frequently have chest radiographic findings that are nottypical of pulmonary TB. Atypical radiographic findings increase the potential for delayed diagnosis whichincreases transmission.Indoor environmentTransmission is rarely thought to occur outdoors. Risk of transmission is greatest where there is prolonged,close contact with a case in an indoor environment; small volumes of shared indoor air, limited ventilationof the airspace with outdoor air and recirculation of air in closed circulation heating or air conditioningsystems. Indoor environments that are poorly ventilated, dark or damp, can lead to increased concentrationand survival of M. tuberculosis. 285-287Duration of exposure 281;288-290The likelihood of transmission of M. tuberculosis increases with the intensity, frequency and durationof exposure to a case. Usually it takes many hours or days to transmit an infectious dose, but casual/short exposures may lead to transmission if the case is infectious and environmental air conditions arefavourable. 291 Exposure duration of less than eight hours is generally considered not to be significant.Current US and UK guidelines 26;51 cite cumulative contact of eight hours or more for contact investigation.8.2 Initiating the Contact InvestigationPrompt notification of active TB cases is crucial, allowing for the early initiation of contact tracing (table8.2). Rapid evaluation of close contacts allows timely identification of those who have active disease and, ifactive disease has been excluded, allows initiation of treatment of LTBI for newly infected contacts beforedisease occurs.-96-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTable 8.2: Timeframes for completing various stages of the contact investigationCase notificationCase should be notified as soon as possible, and not later than oneworking day following diagnosisContact tracing interviewShould be conducted no later than:o 1 working day after notification of an infectious/presumedinfectious caseo 3 working days after notification for all other pulmonary andextra-pulmonary casesSite investigationShould be conducted no later than 3 working days after the contacttracing interview if deemed appropriate following a risk assessmentFirst screening of prioritycontactsShould be conducted no later than:o 7 working days for close contacts of an infectious/presumedinfectious caseo 14 working days for all other contacts (i.e. casual contacts ofinfectious cases/contacts of non-infectious cases) after thecontact tracing interview8.3 Investigating the Index CaseComprehensive information regarding an index patient is the foundation of a contact investigation. Whena case of TB is identified, detailed information about the index case should be collated and considered, sothat priorities can be established for screening. Criteria for consideration are multiple and include:• Anatomical site(s) of TB disease• Symptoms and date of illness onset• Chest X-ray results (and other results of diagnostic imaging studies)• Diagnostic specimens that were sent for bacteriological or histological analysis• Current bacteriological results• Previous diagnosis/treatment for TB infection or disease• Concomitant medical risk factors/conditions• Relevant socio-demographic information• Names of contacts and• Exposure locations.The MOH (in practice regional director of public health/designated medical officer) is responsible forconducting TB contact investigations. Local standard operating procedures for investigation improvethe efficiency and uniformity of investigations. Timeframes for completion of specific stages of contactinvestigation are recommended in table 8.2.Determining the infectious periodDetermining the infectious period focuses the investigation on those contacts most likely to be at risk forinfection and sets the timeframe for testing contacts. Cases of pulmonary TB are generally considered tobecome infectious at the time of onset of cough. If no cough is reported or if the duration is difficult todetermine, the time of onset of other symptoms attributable to TB may be used to estimate the onsetof infectiousness. In practice, however, it is often difficult to know with certainty when symptoms began.Because the start of the infectious period cannot be determined with precision by available methods, apractical estimation is necessary.For infectious/presumed infectious cases: (see table 8.1) assessment of the period of exposure shouldextend to three months before symptom onset or first positive finding consistent with TB disease (e.g.abnormal chest X-ray), whichever is longer. This is consistent with recent guidelines published by the USCenters for Disease Control and Prevention 51 and Canada. 30For cases other than infectious/presumed infectious cases: assessment of the period of exposure should-97-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCextend to four weeks before the date that TB was suspected. Again, this is consistent with current CDC30, 51and Canadian guidelines.The decision about the period of infectiousness, therefore, will need to be determined for each caseaccording to these guidelines and to the clinical situation. Priority should always be given to contacttracing during the period when the TB patient was symptomatic. If the yield of contacts with active diseaseis found to be higher than expected from tuberculin testing, the period of potential exposure should befurther extended.The period of time in which a patient on effective therapy takes to become non-infectious varies. This canbe established in infectious pulmonary patients by monitoring susceptibility to treatment (as demonstratedby smear negative sputum results on three consecutive days) 30, 51, 52 and diminished symptoms. 51 RespiratoryTB patients are usually non-infectious after a minimum of two weeks of treatment. 268.4 Prioritisation of ContactsAs the circumstances in each contact investigation are unique, and risk of infection and disease toindividual contacts cannot be determined precisely, the classification of contacts into ‘close’ and ‘casual’is recommended to guide the decision making process (see table 8.3). Contacts with a cumulative totalexposure to an infectious TB case exceeding eight hours within a restricted area should be regarded asclose contacts i.e. equivalent to household contacts. A reduced cumulative total exposure time of ≥ 4hours should be considered for vulnerable contacts such as young children aged less than 5 years andimmunocompromised contacts.Table 8.3: Classification of contacts for prioritising contact tracingDescriptionContact classificationClose contacts• All household contacts (an individual sharing a bedroom,kitchen, bathroom, or sitting room)• All other immunocompetent adult contacts with a cumulativetotal exposure ≥ 8 hours in a restricted area equivalent toa domestic room (may include girlfriend, boyfriend, closefriends, sexual partners, frequent visitors to the home, etc.)• A reduced cumulative total exposure time of ≥ 4 hours mayneed to be considered for vulnerable contacts exposedin a restricted area such as children aged < 5 years andimmunocompromised individuals, immunocompromised eitherdue to disease e.g. HIV or therapies, individuals receiving>15mg prednisone or equivalent for more than four weeks, orother immunosuppressive agents for cancer, chemotherapeuticagents, anti-rejection drugs for organ transplantation andTNF-α antagonists or as defined by the attending consultant.• Individuals exposed during medical procedures (e.g.bronchoscopy, sputum induction or autopsy) where noinfection control practices were in placeCasual contacts• Generally all other contacts such as work colleagues, team/club members, etc. (some such contacts may be assessed asbeing close contacts following risk assessment)For infectious/presumed infectious cases (see table 8.1): all close contacts should be screened initially.Screening should be extended if there is evidence of infection or disease in close contacts followingscreening i.e. evidence of transmission.For cases other than infectious/presumed infectious cases: Screening should be limited to householdmembers only unless there is evidence of recent infection (e.g. TB in child) and the source remains-98-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCunknown. In such circumstances, screening by chest X-ray should be considered for those adults in regularcontact with the child (e.g. childminder, teachers).BExpanding a contact investigationConsideration should be given to extending screening if there is evidence of transmission based on any ofthe following:• There is an unexpectedly high rate of infection or TB disease in close contacts (e.g. if ≥10% of closecontacts have TB infection or active disease) 51• TB disease is identified in a casual contact or a contact with low screening priority• Infection is identified in any contact (close/casual) under five years of age.8.5 The Contact Tracing InterviewA newly diagnosed patient should be interviewed by a trained member of staff in the hospital, TB clinic,in the patient’s home or anywhere that will ensure the patient’s privacy. Interviews should be completedas soon as possible (see table 8.2). The interview provides an opportunity to exchange information, forthe patient to acquire information about TB and its control, and for the health professional to learn toadapt treatment and education strategies to the patient’s specific requirements. The Centers for DiseaseControl and Prevention (CDC) developed standard procedures for interviewing TB patients in 1999. 292 Thefollowing principles as proposed by CDC are recommended for use:1. Building rapport with a case is an important part of contact tracing. This can be achieved byassuring patient privacy, helping the patient decide how to share information about their diagnosisto contacts, and allowing approximately one hour for exchange of information (depending on thepatient’s health and endurance).2. Exchanging information should allow the interviewer to obtain missing information e.g. date ofsymptom onset, and the patient to improve their understanding of disease causation/transmissionand clarify their treatment plan requirements.3. Transmission settings i.e. places the case attended while infectious should be identified socontacts attending those venues can be identified and prioritised for screening based on timespent by the index case in those settings. Topics for discussion could include where the patientsworked, spent their leisure/recreational time, where they visited, ate, spent nights, etc. Theinterviewer should ask specifically about time spent in congregate settings (e.g. schools, prisons,hospitals/healthcare settings, etc.)4. Lists of contacts should be made for those attending each potential site of transmission, includingname of contact, approximate types, frequency and duration of exposure. Recent illness amongcontacts should be discussed.5. Closure: The interviewer should express appreciation for the patient’s contribution, and indicatehow screening will proceed, that site visits will be conducted and confidentiality respected.6. Follow-up interviews should be scheduled if further information is required.Site investigationSite visits may need to be undertaken to complement interviews. It is important that consideration is givento the index case’s lifestyle so that places of intense contact other than the household may be determined(e.g. work or leisure sites). Site visits may add contacts to the list and are the most reliable source ofinformation regarding transmission settings. 288 Physical conditions at each setting can contribute totransmission. At congregate settings, the size of the room(s), ventilation system and airflow patterns shouldbe considered along with information about how long and how often the patient was in that setting. Failureto visit all potential sites of transmission has contributed to TB outbreaks. 293;294 Visiting the index patient’sresidence is especially helpful for finding children who are contacts. Certain sites (e.g. congregate settings)require special arrangements to visit. Communication and liaison with management in congregate settingsis an essential component of site investigation. Maintaining confidentiality for an index patient can bedifficult. The index case should be informed that information needs to be shared with management. Everyeffort should be taken to maintain patient confidentiality.-99-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC8.6 Screening ToolsThe TST using the Mantoux technique (2TU) is the primary tool used in contact tracing 295 (chapter 2). IGRAtesting is an additional diagnostic method for screening of LTBI.Guides to evaluating contacts of active TB cases are shown in figures 8.1 (for contacts of active TB cases)and 8.2 (for children between four weeks and five years who are contacts of infectious TB cases). Theseguidelines do not fit every circumstance and additional considerations beyond those discussed in theseguidelines may need to be taken into account for specific situations. It is important to monitor attendance,to identify those contacts who fail to attend and to ensure that the contact’s GP is informed of repeatedfailures to attend.In the future, the rapidly expanding evidence base will provide more reliable information on the sensitivityand specificity of IGRA tests and their comparability to the TST. Evidence gathered to date suggests thatthe IGRA tests are at least as sensitive as the TST in diagnosing LTBI and more specific in populations thatinclude previously BCG vaccinated individuals. However, discordant results between IGRA and the TSThave been observed, leading to difficulties interpreting the results. 60In theory, a two-step strategy, using TST (with its high sensitivity) followed by IGRA testing (with its highspecificity) should be an optimal approach for screening an individual exposed to a TB case. 26 The chestX-ray is generally reserved as a means of confirming pulmonary disease following recent contact with TB orin the presence of suggestive symptoms.Canadian guidelines 60;296 on IGRA published in 2007 and updated in 2008 summarised current evidence inthe context of contacts of a case of infectious TB and IGRA use as follows:• IGRA correlated with exposure better than TST in BCG vaccinated contacts. There weresignificantly fewer positive results in low-exposure groups with the IGRA than with the TST• In the absence of BCG, the IGRA and TST appeared to have similar rates of positivity, althoughthere were discordant results.Those guidelines conclude that, given that several studies have found significant discordance between TSTand IGRA results (both TST positive/IGRA negative and the reverse) and because the biological basis of thisdiscordance is uncertain, the reliance on IGRA should depend on the clinical context.The Canadian guidance with regard to IGRA use in contact tracing is recommended.Canadian guidance on IGRA for adult and child contacts of a case of active infectious TBtuberculosis 60IGRA may be used as a confirmatory test for a positive TST in contacts (adult or child) who onthe basis of an assessment of the duration and degree of contact with an active infectious caseare felt to have a low pre-test probability of recently acquired LTBI and who have no otherhigh or increased risk factors for progression to active disease if infected.For close contacts or those contacts who have high or increased risk of progression to activedisease if infected, a TST (or both TST and IGRA) should be used and if either is positive thecontact should be considered to have LTBI.If both TST and IGRA testing will be used, it is recommended that blood be drawn for IGRA onor before the day when the TST is read.Repeating TST in contact investigationsThe interval between acquisition of infection and tuberculin conversion is an important issue. Thisdetermines the interval between the first and second TST in contact investigations i.e. the so-calledwindow period. Traditionally this had been considered to be 12 weeks but all available evidence from-100-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCBCG vaccination and natural infection points to a shorter interval. After inadvertent vaccination with M.tuberculosis (the Lubeck Disaster), children developed positive reactions in three to seven weeks. Otherstudies have shown clinical illness with a positive tuberculin test from 19-57 days after exposure with amean of 37 days. 297There continues to be international variation in practice. The 2003 New Zealand TB Control guidelineslowered the window period for testing from twelve to eight weeks based on the findings of the studiesoutlined above. 52 Current US guidelines 51 cite eight to ten weeks, while the UK advises a six-week intervalbetween tuberculin tests (a recommendation based on consensus opinion of clinicians and experts). 26It is the view of this committee, based on available best evidence, that six-eight weeks constitutes agood timing interval as it is important to leave long enough for conversion to occur but not too long for adelayed diagnosis. Eight weeks is a good compromise and well within evidence for conversion times statedin the literature.Recommendation:The recommended interval between first and second screening rounds (TST ± IGRA) in contactinvestigations is eight weeks. If the last contact with the infectious case exceeded an eightweekperiod, one TST is sufficient.-101-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCFigure 8.1: Algorithm for close contacts (adults and children ≥ 5 years) of all cases of infectious/presumed infectious TBFor all at outset:• Medical history• Physical examinationIf relevant symptoms:• Sputum for microscopy & culture• Chest X-rayAny abnormal chest X-ray:Refer for full evaluation for TB diseaseMantoux 2TUNegative (0-5mm)Positive (6-9mm)Positive (≥ 10mm)Non-infectiousindex caseInfectiousindex caseCXR negativeCXR negativeNoContact withcase withinprevious 8 weeksNon-infectiousIndex caseInfectious indexcaseNon-infectiousIndex caseInfectiousindex caseDischargeInform andadviseConsiderBCG if ≤35yearsYesRepeat TST orTST and IGRAMantoux conversion(≥ 5mm increase) orIGRA positiveCXR negativeConsider IGRAregardless ofBCG statusContact withindex case withinprevious 8 weeksNoIf no BCG: LTBI treatment*If BCG vaccinated:consider IGRAIGRA positive: LTBItreatmentIGRA negative: Informand adviseYesIf no BCGLTBItreatment *Repeat TST orTST and IGRAIf TST (≥10mm)or IGRA positiveand repeat CXR isnegative: LTBItreatment*IGRA ifBCGvaccinated &Mantoux

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCContact investigation for patients whose culture converts back to positiveIn some instances, a TB patient’s culture may convert to negative and then become positive again. Thismay happen if a patient is lost to follow-up and discontinues medications before completing treatment or iftreatment was not adequate because of multidrug resistance.If the patient is located after a treatment lapse of three months or longer and if the patient’s cultures havebecome positive again or if the patient relapses while on treatment after becoming culture negative, asecond window period should be defined and the patient should be re-interviewed. Contacts identifiedduring the initial investigation should be re-evaluated if they were exposed again. If new contacts areidentified, they should be tested and evaluated. 77Contact investigation among children and adolescentsContact investigations for children with suspected TB are generally conducted to identify the adult sourcecase.Because TB among infants and young children usually occurs within weeks to months of contractinginfection with M. tuberculosis, having a child with disease is a marker of recent transmission from someonein the child’s environment. 51 Children younger than 10 years with pulmonary TB are rarely contagiousbecause their pulmonary lesions are small (paucibacillary disease), cough is not productive, and few or nobacilli are expulsed. 109 However, children or adolescents of any age with characteristics of adult-type TB(i.e. productive cough and cavitary or extensive upper lobe lesions on chest X-ray) should be consideredpotentially infectious at the time of diagnosis. 51A negative TST does not exclude LTBI or TB disease. Approximately 10 to 15% of immunocompetentchildren with culture-documented disease do not react initially to a TST. 109 Host factors such as youngage, poor nutrition, immunosuppression, other viral infections (especially measles, varicella and influenza),recent TB infection and disseminated TB disease can decrease TST reactivity. Many children and adults coinfectedwith HIV and M. tuberculosis do not react to a TST.In the interpretation of a positive TST among child contacts of contagious TB cases, current US guidelinesdisregard previous BCG immunisation. 109Young child contacts aged under five years of an infectious TB caseFollowing exposure to a case of infectious/presumed infectious TB, children should have a TST and anevaluation for TB disease (chest X-ray and physical examination). Once active TB has been ruled out,children with positive skin tests should receive a full course of treatment for LTBI (chapter 3). Thosewho have negative skin test results should also receive treatment for presumed LTBI (chapter 3). Thisintervention is especially critical for infants and toddlers < 3 years but is recommended for all children aged< 5 years. 51 Those with a negative TST result should be retested eight weeks after exposure to infectiousTB has ended. If the TST result is still negative in an immunocompetent individual, isoniazid can bediscontinued (continue for further 7 months i.e. a total of 9 months if immunocompromised). If the secondtest is positive, treatment should be continued for a further 7 months i.e. a total of 9 months. 51;109-103-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCFigure 8.2: Algorithm for children aged between four weeks and five years who are closecontacts*of infectious/presumed infectious TB casesNote:For all at outset (regardless of BCG status)• Medical history• Physical examination.• Chest X-rayIf relevant symptoms or chest X-ray abnormalRefer to consultant paediatrician for fullevaluation for TB disease≤ 5mmIsoniazid 10mg/kgand Mantoux 2TU>5mmContinue IsoniazidRepeat Mantoux (8 weeks)Mantoux >5mmYesNoYesAssess for clinicaldiseaseNoStop IsoniazidAdvise BCG ifunvaccinatedTreat andnotifyLTBItreatmentJanuary 2014: The following amendment has been made to Figure 8.2: “Mantoux > 5mm AND increase on initial test > 5mm”changed to “Mantoux > 5mm”.The algorithm presented here is a guideline only and should be interpreted in accordance with the clinicalcontext.Note: IGRA may be considered on a case by case basis as per the general recommendations in section 2.6.Management of newborn infant contact of TB 109Management of the newborn infant is based on categorisation of the maternal (or household contact)infection. Although protection of the infant from TB disease is of paramount importance, contact betweeninfant and mother should be allowed when possible.Mother (or household contact) with TB diseaseInvestigation of all household members should be conducted without delay. If the mother has TB disease,the infant should be evaluated for congenital TB. The mother (or household contact) and the infant shouldbe separated until the mother (or household contact) has been evaluated and the mother (or householdcontact) and infant are receiving appropriate anti-TB therapy, the mother wears a mask, and the motherunderstands and is willing to adhere to infection control measures. Once the infant is receiving isoniazid,separation is not necessary unless the mother (or household contact) has possible MDR-TB or has pooradherence to treatment and DOT is not possible.If congenital TB is excluded, it is recommended that isoniazid is given until the infant is three months ofage, when a TST should be performed. If the TST result is positive, the infant should be reassessed for TBdisease. If TB disease is excluded, isoniazid should be continued for a total of nine months. The infant* See Table 8.3 for definition of a close contact-104-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCshould be evaluated at monthly intervals during treatment. If the TST result is negative and the mother (orhousehold contact) has good adherence and response to treatment and is no longer contagious, isoniazidcan be stopped. BCG vaccine should then be given provided there are no contraindications.See chapter 5 for information on anti-TB medications in breastfeeding women.8.7 TB OutbreaksA TB outbreak indicates potential extensive transmission. An outbreak implies that the patient wascontagious, that contacts were exposed for a substantial period and that the interval since exposure hasbeen sufficient for infection to progress to disease (chapter 1). An outbreak investigation involves severaloverlapping contact investigations, with a surge in the need for public health resources.Outbreak definitionDefinitions of TB outbreaks are relative to the local context. In general, two or more apparently relatedcases of TB constitute an outbreak until proved otherwise. 298 Outbreak cases can be distinguished fromother cases only when certain associations in time, location, patient characteristics or M. tuberculosisattributes (e.g. drug resistance or genotype) become apparent. In low-incidence areas, any temporalcluster may be suggestive of an outbreak. In places where cases are more common, clusters can beobscured by the baseline incidence until suspicion is triggered by a noticeable increase, a sentinel event(e.g. paediatric cases) or genotypically-related M. tuberculosis isolates. Outbreaks of TB are statutorilynotifiable under the Infectious Diseases (Amendment) (No.3) Regulations 2003 (S.I. No.707 of 2003). 21Outbreak managementThe primary objectives of outbreak management are to:• Recognise the outbreak• Define its epidemiological characteristics and aetiology• Prevent its further spread and recurrence and• Maintain satisfactory communications with appropriate external agencies and the general public.For efficient and effective management of an outbreak, an outbreak management plan should be basedon the principles that the director of public health/consultant in public health medicine has overallresponsibility for investigation and control and for managing the outbreak and that individual members ofthe outbreak control team (OCT) have responsibility for managing clearly defined aspects of the outbreak.Suitably developed plans should be agreed between the relevant stakeholders in each HSE area.Outbreak control teamAppropriate representation on the OCT is crucial. In outbreaks affecting more than one area the chairshould be agreed.The main objectives of the OCT will include:• To investigate the source/cause of the outbreak: epidemiological study including:- formulation of hypothesis to explain the most likely source, site and time of infection- case definition and- case finding (identifying numbers affected/exposed). Methods will vary according tonumbers involved and the setting in which the outbreak has occurred. Molecular typingmay be of assistance.• To agree on the implementation of any measures necessary to control the outbreak including theidentification and referral of cases, the screening of contacts and other measures as appropriate(e.g. chemoprophylaxis and referral). Potential resource implications will require estimation andaddressing.• To monitor the effectiveness of control measures• To provide information to patients, patients’ contacts, GPs, the general public, the media andappropriate staff• To liaise with appropriate health bodies and statutory services• To coordinate the investigation, evaluate the overall work of controlling the outbreak andimplement the lessons learned and• To produce interim reports as required and a final outbreak report at the conclusion of theoutbreak.-105-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCCommunicationsCommunications often present an intensely challenging aspect of outbreak investigation and management.TB outbreak investigations can be complex and protracted. Communications may extend over lengthyperiods. Apart from providing regular information to patients, contacts and their families, there are alsoregular professional and media aspects to be addressed. All media communications should be coordinatedby the press officer. The setting up of a helpline to give specific advice and information may need to beconsidered.8.8 Congregate SettingsOverall concerns associated with congregate settings include:• The substantial numbers of contacts• Incomplete information regarding contact names and locations• Incomplete data for determining priorities• Difficulty in maintaining confidentiality• Collaboration with officials and administrators who are unfamiliar with TB• Legal implications and• Media coverage. 51Increased resources will be necessary when the scope or duration of an investigation is expected to disruptother essential TB control functions.Maintaining confidentiality for an index patient is particularly challenging if the patient was conspicuously illor was absent from the setting while ill. Collaboration with officials at the setting is essential for obtainingaccess to employee and occupancy rosters, ascertaining contacts, performing on-site testing and offeringeducation to associates (e.g. classmates, friends or co-workers) of the index patient. (see site investigation,section 8.5). For congregate settings, the types of information for designating priorities are site specific,and therefore a customised algorithm is required for each situation. The general concepts of source-casecharacteristics, duration and proximity of exposure, environmental factors that modify transmission, andsusceptibility of contacts to TB should be included in the algorithm. The optimum approach for a settingbasedinvestigation is to interview and test contacts on site. If this is not possible, then the contacts shouldbe invited for evaluation at a designated health facility.8.9 WorkplacesMany people spend the majority of their waking hours in their workplaces. Duration and proximity ofexposure can be greater than for other settings. Details regarding employment, hours, working conditionsand workplace contacts should be obtained during the initial interview with the index patient, and theworkplace should be visited and examined after accounting for confidentiality and permission fromworkplace administrators or managers. Employee lists are helpful for selecting contacts, but certainemployees might have left the workplace and thus have been omitted from current employee lists.Customers of a business workplace may also need to be considered. 51Workplace administrators or managers are likely to express concern regarding liability, lost productivity andmedia coverage. In addition, they might have limited obligations to protect patient confidentiality. All ofthese issues can be addressed during the planning phase of the investigation.8.10 Hospitals and other Healthcare SettingsThe primary TB risk to other patients and staff in hospitals/healthcare settings is the undiagnosed orunsuspected patient/staff member with infectious TB disease. The issue of potential exposure of patients,some of whom may have reduced immunity, may result in considerable resources being directed atidentifying exposed patients many of whom are likely to be at minimal risk. Unnecessary screening ofcontacts with minimal risk should be avoided as yields from contact investigation in healthcare settings canbe low. 299-301Healthcare-associated transmission of M. tuberculosis has been linked to close contact with persons-106-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCwith TB disease during aerosol-generating or aerosol-producing procedures, including bronchoscopy,endotracheal intubation, suctioning, other respiratory procedures, open abscess irrigation, autopsy, sputuminduction and aerosol treatments that induce coughing. 229Effective contact tracing requires liaison between public health services, hospital infection prevention andcontrol and occupational health services. Coordination of contact tracing is most appropriately led byhospital infection prevention and control (vis. consultant microbiologist) in those healthcare settings wherethis is in place. This will include the initial alerting of public health and occupational health services. In allother healthcare settings, coordination should be undertaken by the public health service.Contact tracing should be initiated where: 229• A person with infectious TB has been examined at a healthcare setting, and TB disease was notdiagnosed and reported quickly, resulting in failure to apply recommended TB infection controlsor• Environmental controls or other infection control measures have malfunctioned while a personwith infectious TB was in the settingor• A HCW develops infectious TB and exposes other persons in the setting.Contact tracing should be carried out only for patients for whom the risk is regarded as significant. Notwo episodes of this kind are likely to be identical in all respects, and narrowly drawn guidelines are thusinappropriate. A repeat risk assessment should also be made if investigation of the household contacts ofthe index case has an unusually high yield.Guidance for contact tracing in hospitals and healthcare settings:1. 8Infectious TB in a hospital inpatient• Following diagnosis of infectious TB in a hospital inpatient in an open ward, a risk assessment shouldbe undertaken. This should take into account the degree of infectivity, the length of time beforethe infectious individual was isolated, the proximity of the contact, and whether other patients wereunusually susceptible to infection• In general, patients should be regarded as at risk of infection if they spent more than eight hours inthe same section (rather than the whole ward) as an inpatient with infectious/presumed infectiousTB (see table 8.1). 302 If patients were exposed to a patient with infectious/presumed infectious TBfor long enough to be equivalent to household contacts (as determined by the risk assessment), oran exposed patient is known to be particularly susceptible to infection, they should be managed asequivalent to household contacts (see figure 8.1) 26• Where an inpatient has MDR-TB, or if exposed patients are immunocompromised, specialist expertadvice should be sought• Staff in casual contact with a case of smear positive TB should be reassured and reminded of thepossible symptoms of TB to report. Staff who have undertaken mouth-to-mouth resuscitationwithout appropriate protection, prolonged care of a high dependency patient or repeated chestphysiotherapy on a patient with undiagnosed respiratory TB should be managed as close contacts. 3022. Infectious TB in a HCW• If the HCW has been at work while infectious, it will be necessary to identify patients, other staff andvisitors who may have had significant contact and manage as per contact tracing procedures.Other healthcare settingsElderly people residing in nursing homes are almost twice as likely to acquire TB as those living inthe community. Certain considerations for control of TB in hospitals apply also to such extended carefacilities, 229 including maintaining a high index of suspicion for the disease, promptly detecting casesand diagnosing disease, isolating infectious persons and initiating standard therapy and identifying andevaluating contacts (contact investigation).-107-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC8.11 SchoolsThe notification of a case of TB in a school setting, whether a staff member or pupil, requires particularattention because of the potential for spread of infection and also because of the anxiety that can begenerated among pupils, parents, staff and the wider public. The typical features of contact investigationsin schools are the potentially substantial numbers of contacts and difficulties in assigning priorities tocontacts who have undetermined durations and proximities of exposure.If the index case is a staff member, the aim of contact tracing is generally to detect secondary cases in theschool. This may also be the aim if the index is an infectious adolescent case. If the case is a younger childor a non-infectious adolescent, the main purpose is to detect a source case in addition to the possibility ofdetecting other secondary cases from a common source.The NICE guidelines 26 attempted to establish whether contact tracing was effective in identifying latentand active TB in school contacts exposed to an index case of TB in the school setting. It found potentialdifficulties in making recommendations from the identified evidence base including the possibility ofpublication bias, the fact that the evidence base did not take into account the country of birth or ethnicityof pupils (likely to be a confounding factor), noting that many of the studies conducted outside the UKwere carried out in non-BCG vaccinated populations, and that rates of disease were calculated on smalldenominators and were therefore imprecise. The guidelines here are broadly similar to those produced bythe NICE guideline development group.Guidance following notification of a case of TB in a pupil or staff member:• Case risk assessmento The case risk assessment should include an early visit to the school to check indoor spaces,observe general conditions and enquire about ventilation.• Communicationo Early meeting with school management to explain prevention and control measureso Early consideration of how to best communicate with the wider school population and howto keep updatedo Early anticipation of, and planning for, media communication aspects. The presence ofTB in schools often generates publicity. Ideally, the public health department shouldcommunicate with the school and parents (and guardians) before any media report a story.• School pupil with infectious/presumed infectious TBo Screen class (if single class group) or year (who share classes)o Screen relevant staff members (class teachers/games/school bus/other)o Screen (by symptom enquiry and single chest X-ray) all other members of staff in the schoolif the index case of a school pupil’s TB infection is not found. This is especially relevant ifevidence of recent infection has been found in fellow pupils in order to exclude a potentialindex case among staff.• School pupil with non-infectious TBo Consider screening by symptom enquiry and single chest X-ray all relevant membersof staff (in order to exclude a potential index case among staff) in the school (relevantteaching/games/school bus/other) if the index case of a school pupil’s TB infection is notfound among household members or other immediate contacts outside of school.• Teacher with infectious/presumed infectious TB (i.e. including BAL positive)o Screen, where in contact during preceding three months, relevant class pupils/games etc.o Screen staff member contacts.• Teacher with non-infectious TBo Consider screening other adults in the school by symptom enquiry if the source (indexcase) is not found outside the school. Otherwise no contact tracing indicated in the school.• Screening extensiono Contact tracing may need to be extended to include children and teachers involved inextracurricular activities (e.g. sport, school bus travel, etc.) and non-teaching staff on thebasis of degree of infectivity of index case/length of time the index case was in contactwith others/whether contacts are unusually susceptible to infection/the proximity ofcontact. Outdoor activities would not normally pose a transmission risk, unless this involvedconfined spaces for prolonged time periods.-108-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• Secondary caseso Any secondary cases of sputum smear positive TB should be treated as index cases for thepurposes of contact tracing.• Further pupil case within 12 monthso Should a further case of TB occur in a child within a twelve month period, all adult staff inthe school should be screened with a single chest X-ray (in order to exclude a potentialindex case among staff).Pre-schoolsChildren aged < five years who have been identified as contacts of cases of infectious TB should receivea clinical evaluation, including a TST and chest X-ray, to rule out active TB. TB disease in children aged

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCsputum smear negative. Patients with MDR-TB or XDR-TB should not travel until they have been provedto be non-infectious (i.e. culture-negative). Health authorities and/or physician(s) should conduct a riskassessment of the potential infectivity, potential drug resistance, duration of the proposed flight, and thepossible consequences of transmission to other passengers when a TB case wishes to travel. The publichealth authority and/or physician must give clear advice or instruction on whether or not to travel. Patientsintending to travel against this advice should be reported to the MOH of the relevant HSE area for anynecessary action. 3031. Contact tracing of infectious or potentially infectious TB cases on aircraft should be limited toflights which were ≥ 8 hours duration and took place during the previous three months. Allcases of respiratory TB who are sputum smear positive and culture positive (if culture available)are deemed infectious. All cases of respiratory TB who are sputum smear negative and culturepositive are deemed potentially infectious. The following criteria should also be used whendetermining the infectiousness of a case at the time of travel: (i) presence of cavitations on chestX-ray, (ii) presence of symptoms at the time of the flight and (iii) documented transmission toclose contacts.2. If the index case is a passenger, obtain contact details of passengers sitting in the same row andthe two rows ahead and behind (from one side of the aircraft to the other because of ventilationpatterns) the index patient. Inform contacts of possible exposure and advise screening of theseflight contacts and cabin crew who serviced the section in which the TB case was seated.3. If the index case is an aircraft crew member, contact tracing of passengers should not routinelytake place. Contact tracing of other members of staff is appropriate, in accordance with theusual principles for screening workplace colleagues.Table 8.4: WHO recommendations for contact tracing of infectious TB cases on air flights ≥ 8 hours 303Clinicians should immediately inform the MOH in the relevant HSE area of any patients with infectiouspulmonary or laryngeal TB who have a history of air travel ≥ 8 hours.The MOH should then inform HPSC of the case. Case and air flight details should also be forwarded toHPSC. HPSC will then verify with the airline(s) that:1. The patient was on the flight2. The flight time (≥ 8 hours) and3. ≤ three months have elapsed since the flight.If the TB patient travelled on more than one airline, HPSC will contact each airline on which the patienttravelled on a flight for ≥8 hours total flight duration.Once this is verified, HPSC (as country where the case was reported) will then inform the counterpartpublic health authorities in all countries where the flight(s) departed and landed. HPSC will then requestfrom the airline(s) the list of relevant flight contacts outlined in figure 8.3 and will also inform the publichealth authorities of the countries of residence of the identified contacts and advise them of the situation.In countries of residence of the contacts, the public health authorities should follow national policy forTB contact investigation. In some circumstances such cases (as outlined in the WHO TB and Air TravelGuidance) may need to be reported to WHO under the International Health Regulations (IHR). 303Recommendations on the prevention and control of TB transmission on aircraft is based on best currentlyavailable scientific evidence and medical practice. Over time, if new evidence emerges in relation to this, itwill be reviewed by the committee and the recommendations revised if deemed appropriate.8.13 PrisonsPrisons are a significant reservoir of infection. 307 Infected inmates can spread TB both within the prison andin the community after release. A 2002 survey of the WHO European region found a mean notification rate-110-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCof 232 new cases per 100,000 prisoners (range: 0-17,808). Highest rates were observed in countries of theformer Soviet Union, and have been attributed to overcrowding, poor hygiene and ventilation. 308Outbreaks of TB have been reported in prisons in the US and UK. 15;309 Although TB in prisons was notthought to be a problem in England and Wales in the 1980s, 310 routine surveillance has recently shown anincrease in cases in this setting. Prisons in London have been associated with a large outbreak of isoniazidresistantTB since 2001. 311 In the US, outbreaks have involved MDR-TB in HIV-infected individuals. 309Maintaining control of TB in prisons is challenging because of difficulties with practicalities such as promptdiagnosis of cases, identification of contacts, screening and compliance with prophylaxis and treatment.Contact tracing is typically complex in prison settings due to short stays and mobility of inmates. Amultidisciplinary team, led by the local public health department (who will undertake the contact tracing),should be convened to manage the intervention. 26;312 In addition to key prison staff and prison medicalservices, the team may include other staff who have regular contact with prisoners such as social worker/education worker/probation officer representatives. CDC guidelines highlight the important role ofcorrectional information systems (e.g. an inmate medical record system and inmate tracking system) inefficient contact tracing. 312 Any contacts who are HIV positive or immunosuppressed should be amongthose receiving the highest priority evaluation for infection. 312If a suspect infectious TB case is encountered on contact tracing there should be prompt transfer out ofthe facility for diagnostic evaluation if airborne infection-isolation rooms are not available. If the processis delayed, a substantial number of persons might be exposed as a result of the congregate livingarrangements that characterise correctional facilities.Continuity of care following transfer between prisons and release into the community is seen as a majorbarrier to treatment completion. For this reason, DOT is recommended for all prisoners receiving treatmentfor LTBI and active disease. Prison medical services in liaison with local public health departments areencouraged to make arrangements to facilitate treatment completion. 26Recommendation:A multidisciplinary team approach to effectively manage TB contact tracing in prisons isrequired. This team should be led by the local public health department who will undertakecontact tracing.DOT is recommended for all prisoners receiving treatment for active disease and should beconsidered for those receiving treatment for LTBI.8.14 Other High Risk SettingsHomeless shelters are important sites for transmission of M. tuberculosis and an important cause of thecontinuing high incidence of TB among the homeless population. 313 Contact investigations may be wideranging.Genotyping may help with the rapid identification of clustered cases and sites of transmission.In addition, epidemiological investigations prompted by an increase in the incidence of TB in a communityor by the identification of clusters of cases with identical M. tuberculosis genotype patterns have detectedtransmission in such venues as bars. 314 Transmission has been identified with social activities includingamong persons who drink together in multiple drinking establishments. 3158.15 Incorporating New Approaches to Contact TracingDNA fingerprinting can be used to confirm or disprove suspected linkages between cases. Genotyping alsohelps to identify case clusters that would otherwise not be recognised. 111 The Massachusetts Departmentof Public Health evaluated the impact of DNA fingerprinting on their practice and reported that-111-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCgenotyping identified enough unexpected links and sites not considered by the concentric circle method tojustify consideration of more casual contacts. 316 Genotyping allows earlier recognition of clusters for timelyinvestigation and institution of control measures. All culture positive isolates are eligible for genotyping atthe Irish Mycobacterial Reference Laboratory.8.16 Evaluation of Contact TracingThe evaluation of outcomes from contact tracing is important for evaluating the TB control programme,determining the appropriateness of decisions made regarding the contact investigation and futureplanning. The results of the investigation of each circle of contacts should be evaluated to determine therisk of transmission, attack rates, etc. The following information should be collected: 317• The number of contacts identified (particularly close contacts)• The number of contacts who underwent a full evaluation• The number of contacts diagnosed with active disease• The number eligible for preventive therapy and• The number who accepted and completed preventive therapy.Recommendation:Evaluation of all contact tracing activities is recommended. The following information shouldbe collected: (a) number of contacts identified, (b) number of cases of active disease and LTBIand (c) the number of persons who accepted and completed preventive therapy.8.17 Mycobacterium bovisM. bovis is not frequently isolated from clinical specimens provided by suspected TB patients. Due to milkpasteurisation, the risk of disease from M. bovis infection is negligible. Four to five cases of M. bovis arereported to the National TB Surveillance System (NTBSS) annually (2002-2006). The mean age of cases overthis time period was 62.3 years (range 32 – 86 years).There is little evidence of cattle-to-human or human-to-human transmission of M. bovis in the UK andIreland. The NICE guidelines have advised using diagnostic tests for LTBI in previously unvaccinatedindividuals under 16 years of age who have regularly drunk unpasteurised milk from animals with TB udderlesions. Treatment of LTBI should be offered to those with positive results. All individuals in contact withTB-diseased animals should be informed and advised of the signs and symptoms of TB disease.-112-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC9. Screening in Special SituationsScreening is the practice of identifying a condition or illness, which could benefit from early diagnosis,preventative or curative intervention. 318 Screening should only be undertaken where an illness is sufficientlyprevalent, has a known natural history and appropriate and agreed diagnostic techniques and treatment(s)are available. Illnesses being screened for may not cause symptoms that would lead a patient to seekmedical care of his/her own volition. In addition, there should be an agreed policy on whom to treat andthe cost of screening should be economically balanced.Screening for TB should be focused (‘targeted screening’) on groups or individuals with a greater risk orincidence of TB than the general population, and should be undertaken with the following aims:• To detect and treat active disease, thereby reducing the possibility of transmission to susceptibleindividuals• To identify those with LTBI and offer treatment and counselling as appropriate• To obtain baseline data on TST status for comparison with data from routine surveillance tofacilitate reassessment of levels of risk in high-risk groups.Targeted screening should be conducted depending on local epidemiology and resource availability. It isimportant to be aware that high risk groups for screening may change over time. The committee agreedthat in Ireland, priority groups for screening at this time include:• HCWs• New entrants to Ireland• Prisoners• Homeless individuals and• Persons with HIV infection (chapter 10).9.1 Healthcare WorkersEstimates of the risk of infection in HCWs vary according to time, geographical location, exposure intensityand duration (depending on type of hospital and job category). 319-321 In low-incidence countries, activedisease among HCWs is often associated with non-occupational exposures. 322 Two UK studies reportedthat the risk of active disease in HCWs was two to three times higher than in the general population whenmatched for employment and socioeconomic status. 323;324 A questionnaire-survey of incidents involvingpotential transmission from HCWs found 105 incidents occurred in 2005, which mainly included non-UKborn doctors and nurses, despite occupational screening at employment. Infection is thought to have beenacquired in the past in their country of origin. 325 In 2006, HCWs were found to comprise 5% of all notifiedcases of TB in the United Kingdom, and were more likely to be non-UK born (89%) and female (67%). 14 InIreland, the proportion of annual TB cases reported in HCWs has increased slightly from 5.7% in 2002 to7.3% in 2006 (personal communication, HPSC). Between 2002 and 2006, 68.4% of HCW cases were agedbetween 20 and 40 years of age. Forty-two percent were Irish born individuals with the majority of non-Irish born HCWs originating from India (34.6%), Pakistan (15.4%) and the Philippines (12.8%).Recommendation:A pre-placement screen is recommended for all clinical staff working with patients or clinicalspecimens (this may also be applicable to ancillary staff as determined by a risk assessment).Health questionnaireAll new HCWs should initially complete a pre-placement health declaration undertaken by occupationalhealth which includes screening questions for active TB, details of previous immune status investigationsand BCG status.-113-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCThe following information should be recorded:• Suggestive symptoms• History of BCG (scar check by health professional or documentary evidence of date or ageadministered)• Previous history of TB disease (dates or age, duration and type of treatment, name and address oftreating physician) including family history• Previous TST and result within the previous 5 years if available (documentary evidence of date/age,type of test and result, name and address of treating physician) and• History and details of contact with known cases of TB (date/age, relationship to the case/s, degreeof infectivity of the case). 326Recommendation:If an employee has unexplained and suggestive symptoms such as cough lasting three or moreweeks that is unresponsive to usual interventions and weight loss or fever, a chest X-ray andsputum examination should be carried out. Such employees should not start work. If an employeehas no suspicious symptoms, completion of the pre-placement questionnaire should be followedby an appropriate medical evaluation.Medical evaluationIn the US, CDC recommend that baseline testing for TB is performed for all new healthcare workers,regardless of their occupational risk of exposure to TB. 229 It is the view of this committee that in Ireland,screening of new employees (undertaken by occupational medicine) by TST (2TU Mantoux) should beprioritised as follows:• High priority**** 1HCWs arriving in Ireland (or returning to Ireland) from countries with a high incidence of TB (≥40/100,000 TB cases notified per year).11F Such individuals require a chest X-ray (provided theyare not pregnant) to rule out active TB in addition to a TST (2TU Mantoux test) to detect LTBIregardless of BCG vaccination status (section 9.2). 326• Intermediate priority † † † † ‡ ‡ ‡ ‡ 23HCWs (regardless of BCG status and not in the high priority group ) working in units managingand treating patients with MDR-TB or XDR-TB and patients who are immunocompromised,physiotherapists, laboratory, 327 mortuary, 275 endoscopy and bronchoscopy staff 229,278,328 should allhave a TST (2TU Mantoux test) to rule out LTBI or active TB.• Low priorityIn this group, TST is only offered to those who have no (or inconclusive) evidence of prior BCGvaccine. 326 This group constitutes the vast majority of HCWs. The Mantoux test is undertaken in thissituation to obtain a baseline in case of future exposure in the healthcare setting and to offer BCGvaccine if necessary.1 ****This prioritisation is based both on the increased likelihood of the HCW having TB due to country of origin and because of this theincreased risk of transmission to patients if TB is undetected.2 † † † † This prioritisation is based on both the procedures undertaken by the HCW which increases their risk of contracting TB and alsoon the risk of transmission to immunocompromised patients if the HCW has TB.3 ‡ ‡ ‡ ‡ Healthcare associated transmission of M. tuberculosis has been linked to close contact with persons with TB disease duringaerosol-generating or aerosol-producing procedures including bronchoscopy, autopsy, sputum induction, endotrachealintubation and open abscess irrigation.-114-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCHCWs-Tuberculin Skin TestingRecommendation:HCWs from countries of high TB incidence (≥ 40 cases of TB per 100,000 per year) with apositive TST (Mantoux test) defined as ≥ 10mm (table 2.1) should be referred to a respiratoryor infectious disease clinician (with a chest X-ray) for a medical assessment to rule out TBdisease or LTBI. However, an occupational medicine consultant may wish to treat thesepatients if appropriate protocols, audit of care and resources are in place.Irish HCWs or HCWs from low incidence countries (< 40 cases of TB per 100,000 per year)with a positive TST (Mantoux test) defined as ≥ 15mm (table 2.1) should be referred to arespiratory or infectious disease clinician (with a chest X-ray) for a medical assessment to ruleout TB disease or LTBI. However, an occupational medicine consultant may wish to treat thesepatients if appropriate protocols, audit of care and resources are in place.Treatment for active TB should be considered in HCWs with a positive TST (as outlined above) if the chestX-ray is abnormal, and treatment for LTBI if the chest X-ray is normal and signs and symptoms of diseaseare absent. IGRA testing may be used as a confirmatory test in those individuals with a positive TST.HCWs with active TB should not work while infectious (chapter 6). They will be advised in this regard andwhen to return to work following joint discussion between the treating physician and the occupationalmedicine consultant. The employer will need to consider each case individually taking account ofemployment and health and safety obligations. 329If HCWs with LTBI refuse treatment, the risk of developing TB disease should be explained to themincluding health and safety issues and the oral explanation supplemented by written advice (seeinformation leaflet in appendix 6). In addition, they should be advised to report promptly to theoccupational health department if they become symptomatic. All HCWs should complete an annual healthquestionnaire and be given an annual reminder of the signs and symptoms of TB disease and actionsrequired if they become symptomatic (appendix 6).The following groups should be informed of the signs and symptoms of TB and advised to seek promptmedical attention if they develop these symptoms (see figure 9.1):• Employees from high incidence countries (≥ 40 cases per 100,000 per year) with a TST result ≤10mm• All other employees with a TST result ≤ 15mm.-115-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCFigure 9.1: Algorithm for screening new health care workers (HCWs)Pre-placement questionnaireSymptomatic AsymptomaticRefer for medical evaluationand chest X-rayHigh priority HCW *Intermediate priority HCW **Low priority HCWChest X-ray(if no evidenceof recent ChestX-ray)2TU Mantoux2TU Mantoux15mm - Refer for assessment< 15mm - Inform and advise≤ 5mm and unvaccinated - Consider BCG vaccinationafter risk assessment for HIV infection***2TU Mantoux(Only if no evidence of BCGscar or BCG documentation)AbnormalRefer for medicalevaluationNormal≥10mm - Refer for medical evaluation and consider fortreatment of latent TB infection

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCBCG is indicated for unvaccinated healthcare workers (HCWs) aged

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCreception centres for asylum seekers or by immigration authorities who would in turn notify the relevantHSE areas. Ideally, GPs should refer newly arrived individuals to a combined public health/TB clinic forscreening. New entrants are defined as those who have recently arrived or returned from a country with anincidence of TB of ≥ 40 cases per 100,000 population per year and will be spending at least three monthsin Ireland.Recommendation:All new entrants to Ireland who originate from a country with a high incidence of tuberculosis(≥ 40 cases per 100,000 population per year) and will be spending at least three months inIreland should be provided with an opportunity to be screened for TB.Improved access to care for new entrants and especially illegal migrants is important for TB control. Agood follow-up system is very important to maximise the yield from entry screening. Proper follow-up isneeded to minimise withdrawals during screening and to maximise coverage of the target group as well astreatment adherence. Screening for active TB disease can only be beneficial for public health if treatmentsuccess rates are high. A continuum of TB diagnosis, care and support needs to be offered to new entrantsat high risk for TB. It should also be recognised that TB prevention and control is not the only service thatnew entrants need. Specific TB care should be offered in the context of a holistic approach to ensure thehealth and well being of new entrants.HIV infectionTB is the most common opportunistic infection in HIV-infected individuals. HIV infection acts by weakeningthe immune system, thereby heightening susceptibility to infection and progression to active TB. It is notknown how many new entrants with TB are tested for HIV. WHO initiated their ProTEST initiative (PromoteHIV voluntary counselling and testing) in 1997 to campaign for improved collaboration between TB andHIV programmes. This initiative was aimed at promoting voluntary testing for HIV as a means of ensuring amore inclusive approach to dealing with TB in areas with a high prevalence of HIV.Screening for HIV should be accompanied by culturally sensitive counselling and support (chapter 10).Recommendation:An expanded programme of screening for TB including voluntary screening for HIV in newentrants should be established. The committee believes that this should be part of a broaderhealth screening programme to improve the health of new entrants to Ireland.The 2004 DoHC 332 guidance on ‘Communicable Disease Screening for Asylum Seekers’ recommended thatall new entrants to the Irish health care system undergo screening for TB. This is important as new entrantsare most likely to develop disease within five years of entry and in particular, within the first two years ofarrival. 331 TB screening for active disease and LTBI should be encouraged.Health questionnaireA health questionnaire should be undertaken for all new entrants, and enquire into past history of TBand BCG status, current symptoms, and recent contact with a TB case. All new entrants should completea health screening questionnaire and those with symptoms should be urgently referred to a TB clinic forfurther clinical assessment (chest X-ray and sputum smear direct examination).____________________________________________________§§§§ These countries include Botswana, Cambodia, Djibouti, Lesotho, Namibia, Sierra Leone, South Africa, Swaziland, Timor-Lest,Zambia and Zimbabwe.-118-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCChest X-rayChest X-rays should be offered to all new entrants aged ≥16 years (provided they are not pregnant). Allthose with abnormal chest X-ray results suggestive of active disease or of inactive TB (chapter 2) should bereferred for medical evaluation. Treatment of LTBI should be considered in those with radiological evidenceof inactive TB. Asymptomatic individuals with a normal chest X-ray in a selected group i.e. those aged 16 to35 years from sub-Saharan Africa or a country with a TB incidence greater than 500 per 100,000 §§§§ shouldbe offered a TST (2TU Mantoux test) regardless of BCG vaccination status.TST (Mantoux test)Individuals ≥ 16 yearsAsymptomatic individuals with a normal chest X-ray in a selected group i.e. those aged 16 to 35 years fromsub-Saharan Africa or a country with a TB incidence greater than 500 per 100,000 §§§§4 should be offered aTST (2TU Mantoux test) regardless of BCG vaccination status. Pregnant females (no chest X-ray, see above)should also have a TST (2TU Mantoux test), regardless of BCG vaccination status. A risk assessment forHIV should be undertaken for all individuals having a TST or receiving BCG vaccination which takes intoaccount the HIV rates in the individual’s country of origin.Those with TST results ≥ 10mm should be referred for further medical evaluation and considered forLTBI treatment. Individuals with TST results < 10mm should be informed and advised of the signs andsymptoms of TB disease and asked to seek medical care if they experience these symptoms. Consider BCGvaccination for all those aged ≤ 35 years with TST results ≤ 5mm who are previously unvaccinated (figure9.2 - see page 120).While all age groups should be considered for treatment of LTBI, care should be taken when prescribingLTBI therapy for those with co-morbidities which increase the likelihood of hepatotoxicity. The use of DOTshould also be considered in this population (chapter 3).Individuals

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCFigure 9.2: Algorithm for screening new entrants from countries with ≥ 40 cases of TB per 100,000 perannumAsymptomaticHealthQuestionnaire*SymptomaticReferral to clinic formedical evaluation,CXR and sputumexaminationAge ≥16 years**Age < 16 years orpregnant**2 TU MantouxChest X-rayNormalAbnormalSelectedgroups?***NoInform andadviseRefer for investigation1. If active TB: treat2. If CXR suggestive ofinactive TB: considertreatment for LTBI if notpreviously adequatelytreatedYes2 TU MantouxBCGvaccinatedBCGunvaccinated 500/100,000**** Timing of X-ray and BCG may be dependent on pregnancy status9.3 Prisons, Remand and Detention CentresHigh TB incidence rates 308 and outbreaks associated with multidrug-resistance and HIV co-infection 309;311have been observed in prison populations in recent decades. High rates have been attributed to adisproportionate number of prisoners being of low socioeconomic status, at risk of disease due to alcohol,substance misuse, HIV infection and having recently arrived from areas of high endemnicity (the risk ofdisease development is greatest within five years or arrival). 331 Prison facilities can often be over-crowded,poorly ventilated, with prisoners living in close proximity. 333-336 Short stays and movement between andwithin prison facilities increase the likelihood of exposure to TB patients and enhance the potential fortransmission. This mobility also creates difficulties for the implementation of control strategies. Despitethis, the congregation of many disadvantaged individuals in this setting provides an opportunity to improvethe health of those who may not otherwise receive medical care.-120-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCScreening in prisonsTB screening in prisoners should be provided as part of a routine health professional-led health screeningexercise on entry to prison. The 1996 TB guidelines recommended routine use of a simple questionnaireon entry to prison, followed by chest X-ray to investigate only those with signs and symptoms. 113 Ideally,inmate screening should be undertaken at the beginning of every prison sentence in order to identifyactive cases of disease and latent infection and to initiate treatment before individuals join the main prisonpopulation. 312At a minimum, all prisoners should be screened for symptoms using a health questionnaire at entry.Symptomatic inmates should have a chest X-ray, three sputum samples (at least one of which is a morningsample), and should be isolated from the main prison population until microscopy results can verify theindividual’s sputum smear status. 26 Symptom screening alone is unsatisfactory in facilities where TB hasbeen detected and where factors for increased risk of TB exist (e.g. prisoners with a condition/factorthat increases the risk of TB, environmental factors). 312 Ideally, HIV testing should be offered as part ofroutine health screening for prisoners starting every prison sentence (assists interpretation of TST, also HIVinfection is a contraindication for BCG vaccination). 312A risk assessment should be undertaken to establish an increased risk for TB transmission. Facilities atincreased risk of transmission include the following:• Documented cases of infectious TB have occurred in the facility in the last year• The facility houses substantial numbers of inmates with risk factors for TB (e.g. HIV infection andinjection-drug use) and• The facility houses substantial numbers of new immigrants (i.e. persons arriving in Ireland within theprevious 5 years from countries where the annual TB notification rate is ≥ 40 cases per 100,000). 312If the facility is deemed high risk, then individuals should be screened with a TST (2TU Mantoux test) and ifthis is positive, a chest X-ray will be required. 312Prisoners with a positive TST result or abnormal chest X-ray should be referred to a TB clinic. In congregatesettings, a TST induration of 10mm 312 or greater is considered a positive result (for both prisoners andprison workers) (see table 2.1). An induration of greater than 5mm is positive in:• Persons who are recent contacts of patients with TB disease• Persons with fibrotic changes on their chest radiograph consistent with previous disease• Organ transplant recipients• Immunocompromised individuals (including persons with HIV) and• Persons suspected of having TB disease.Prisoners with a TST result of ≥ 10mm and normal chest X-ray findings should be considered for LTBItreatment. Treatment of LTBI should be administered under medical supervision designated by the prisonservice. If prisoners decline LTBI treatment, a questionnaire screening for symptoms of TB should becompleted annually. Chest X-ray follow-up at three and 12 months is also recommended.HIV-infected or other immunosuppressed inmates (or those with other clinical conditions that renderindividuals at greater risk of latent infection) should have a TST and an IGRA test (which may be consideredin light of false-negative TST results in immunocompromised individuals) to detect LTBI in addition to achest X-ray to rule out active TB disease. 312A multidisciplinary approach to treating a case of active TB disease or LTBI is advised. The decision torefer an infectious case to a tertiary facility should be considered by the treating physician, consultantmicrobiologist, public health and the prison services. Individuals admitted for inpatient care in tertiarymedical facilities should only be discharged back to the prison facility when the patient is deemed noninfectious(as defined in chapter 6).Prison medical services should have liaison and handover arrangements to ensure continuity of care beforeany prisoner on TB treatment is transferred between prisons. 26-121-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendation:A programme of screening for TB in prisoners should be provided.Prisoners should receive chemotherapeutic treatment for active disease or LTBI by DOT, ashigh rates of treatment failure have been observed in this population. 337 Patients undergoingany form of TB treatment should be assigned a key worker (a health professional) to promotecompliance, monitor treatment effectiveness and the occurrence of adverse events. 26Prison medical services should liaise with community TB services to ensure the continuation ofDOT after release from prison.Prison staffNew staff should receive pre-placement screening which is equivalent to screening undertaken for newHCWs. 26 BCG should be offered to prison workers aged 35 years and under 26;255;257 if they are previouslyunvaccinated and tuberculin negative (≤ 5mm) (chapter 7).A high index of suspicion for TB should be maintained in all prisons and prison HCWs should raiseawareness of TB symptoms among prisoners and staff. It is important that prison officers are educatedto recognise the signs and symptoms of TB, the need to seek an early diagnosis by referral, methodsof diagnosis and the effectiveness of treatment, the importance of compliance with TB treatment andmonitoring for adverse events.9.4 Homeless IndividualsElevated rates of TB have been found in homeless individuals in low incidence countries. 338, 339 Many haveconcomitant risk factors for TB such as substance misuse, immunosuppression and malnutrition. High levelsof infectious and drug resistant TB have been observed and poor adherence to treatment regimens andloss to follow up care in this population pose a challenge to TB control. 340 Providing health services to thishigh risk group is problematic, as they are often mobile and hard-to-reach through conventional channels.Therefore, screening in this population should focus on the detection of active disease.Recommendation:An opportunistic active case finding strategy is advised among homeless individuals. Screeningby chest X-ray is recommended. TST and IGRA are believed to be less useful, as people maymove before test reading/results are available. 26Screening on an opportunistic basis and/or symptomatic basis is advised, as is the use of incentives (hotdrinks/snacks). 26 A recommendation on the frequency of screening was not made by the NICE guidelinedevelopment committee due to an absence of evidence, whilst in other European countries, e.g. theNetherlands, illicit drug users and homeless individuals are screened twice per year by digital chestX-ray for two years (this is already used for screening prisoners and asylum seekers). 341 Although routinescreening of homeless individuals is a preferred strategy for detecting disease in this high risk population,it is recognised that this is not always possible. Therefore, screening of homeless individuals in accordancewith UK guidance is recommended. 26 As homeless individuals are at risk of failing to complete treatment,appropriate steps should be taken to encourage compliance.-122-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCRecommendation:Nomination of a key worker for homeless patients receiving treatment and the provision ofDOT are considered an optimal strategy for treatment completion.In addition, statutory and voluntary organisations working with homeless individuals should be educatedabout TB and referral pathways, as this can aid early detection of disease.-123-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC10. TB and HIV InfectionThe management of patients with TB and HIV infection is complex, requiring management by amultidisciplinary team which includes physicians with expertise in the treatment of both TB and HIV. Thischapter provides a broad overview of the management and treatment of HIV-infected individuals withconfirmed or suspected TB or LTBI. Readers are advised to refer to this document together with currentinternational guidelines from the CDC, 342;343 WHO 344 and the British HIV Association (BHIVA). 345Recommendation:Cases of TB/HIV should always be managed by physicians with expertise in treating both TBand HIV.10.1 Epidemiology and Surveillance of TB InfectionTB can occur at any point in the course of progression of HIV infection. It is the commonest opportunisticinfection in HIV-infected individuals and is reported as the cause of death for 11% of all AIDS patients. 2HIV infection acts by lowering the host’s immune response to mycobacteria, heightening susceptibilityto infection and progression to active disease. HIV is recognised as the single greatest risk factor fordevelopment of active TB disease. 6;346;347 The lifetime risk of a HIV and M. tuberculosis-infected individualdeveloping active TB is 50%, ten times greater than a non-infected individual. It is therefore important thata high index of suspicion for TB should be maintained in HIV-infected individuals. 344 It is notable that 63%of AIDS patients with active TB infection have positive blood cultures. 139 Blood cultures should be the firststep in the routine evaluation of HIV positive patients with suspected TB. 140Globally, the number of HIV positive TB cases continues to grow. 1 HIV infection has had a significantimpact on the incidence of TB, particularly in areas where rates are highest e.g. Sub-Saharan Africa.WHO estimates that 9% of all TB cases are co-infected with HIV. Rates are believed to range from 1.1%in the Western Pacific, to 5.9% in the Americas, and to 31% in Africa. 346 In countries with a low incidenceof disease, sub-populations with both infections are recognisable. In the United States, particular ethnicgroups are disproportionately affected, while injecting drug use is a factor in other countries. 348In Ireland, the incidence of TB in HIV-infected individuals is uncertain. This is due to a combination offactors, including the absence of routine HIV screening in TB patients, incomplete reporting of HIV as arisk factor for TB, and non-statutory notification of HIV. TB surveillance data indicate that between 2 and19 cases were known to be infected with HIV per annum (2001-2006) (personal communication, HPSC).However, these figures are an under-estimate due to the factors outlined above.Recommendation:A high index of suspicion should be maintained for TB in all HIV-infected individuals.10.2 PathophysiologyHIV infection destroys CD4 lymphocytes and affects monocyte function, rendering them unable to destroycertain invading microorganisms. HIV produces a progressively deficient immune response and as theinfection develops, CD4 lymphocytes are depleted and immunity to M. tuberculosis is reduced. CD4lymphocyte counts are a useful indicator of the degree of immunodeficiency and clinical features of TB inHIV-infected individuals have been found to correlate with CD4 counts. 349The tubercle bacillus begins its infection in the alveolar macrophage where it multiplies in activated-124-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCmacrophages and leads to cell necrosis. Bacteraemia and secondary spread occurs when the macrophagecannot contain the bacilli. A T-cell mediated delayed hypersensitivity reaction may limit further spread ofbacteria by granuloma formation at initial or regional sites of infection. The destruction of mycobacteriadepends on increases in metabolic and enzymatic activity which is largely dependent on inhibitorymechanisms primed by CD4 lymphocytes.HIV viral replication increases in alveolar macrophages and peripheral lymphocytes when exposed toM. tuberculosis antigens, 350-352 and inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) andinterleukin-1 (IL-1) are mediators of this enhanced replication. HIV acts by destroying lymphocytes andinhibiting the release of lymphokines from CD4 cells which are responsible for recruiting and enhancingmacrophage resistance to mycobacterial replication. The result of the progression of CD4 lymphocytedestruction and consequent effect on macrophages results in poorly formed granulomas and the inabilityto kill ingested mycobacteria and the spread of infection. The results are seen in clinical TB as poorlyformed granuloma, large organism load and blood stream invasion.10.3 Diagnosis of TB in HIV-infected CasesThe diagnosis of TB in a HIV-infected individual may be difficult. The clinical, radiological andhistopathological presentation of HIV-related TB disease can be atypical and is influenced by the degree ofimmunodeficiency. 349;353 Clinical presentation may mimic or co-exist with other opportunistic infections suchas M. avium or Pneumocystis carinii.Evaluation of a suspected HIV-infected TB case should always include a chest X-ray and sputum should beobtained for smear and culture. However, results become less sensitive with increasing immunodeficiency.Bacteriological and histological findingsAs with all TB cases, obtaining appropriate specimens is important for diagnosing HIV-related TB disease.The yield from sputum smear and culture is similar to that in immunocompetent individuals when HIVinfectedindividuals have high CD4 counts. However, in severely immunocompromised individuals, culturepositive sputum is more likely to be smear negative. 354The likelihood of obtaining a positive culture from infected extra-pulmonary sites is greater in patients withadvanced HIV than in HIV-uninfected cases. 355-357 Smear positive specimens from those sites may have alarge burden of bacilli due to an impaired immune response.Histological findings range from typical granulomatous inflammation in individuals with CD4 countsabove 200 cells/μl, to poorly formed/absent granulomas in those with decreasing immunocompetence,particularly in individuals with CD4 counts below 100/μl. In those circumstances, AFB are more likely to beobserved microscopically.Radiological findingsThe spectrum of clinical features associated with TB/HIV positive persons is influenced by the degreeof immunosuppression. Chest X-ray findings of cases with CD4 lymphocyte counts above 350 cells/μl, 342 appear like those of non-HIV infected cases, 343 with disease confined to the lungs with upper lobefibronodular infiltrates and with/without cavitation. Pleural effusions are more common in persons withCD4 counts of > 200 cells/μl. During advanced stages of HIV infection, pulmonary disease may presentwith unilateral or diffuse shadowing in lower and middle lobes or miliary infiltrates on X-ray. Cavitation isuncommon. TB may present as a systemic disease with high fever and sepsis.At CD4 counts lower than 50 cells/μl, extra pulmonary disease (pleuritis, pericarditis, meningitis) becomesincreasingly common (with or without pulmonary involvement). 342 Extrapulmonary disease is detected withgreater frequency in HIV-infected than non HIV- infected individuals, however, the clinical presentation ofextrapulmonary disease does not differ according to HIV status.In patients with severe immunodeficiency, it is not uncommon to have normal chest X-rays and culture andsmear positive sputum specimens. 25-125-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC10.4 Diagnosis of HIV in TB CasesIt is recognised that currently HIV testing may not be undertaken routinely for all TB cases in Ireland. Anoptimal strategy for HIV screening in TB patients would involve all TB patients, regardless of the perceivedrisk of HIV infection, being offered HIV testing as part of their TB assessment. 358 In countries with a lowincidenceof TB, studies have shown that cases of TB/HIV infection have been missed because heterosexualtransmission was not considered as an important risk factor for HIV infection. 359Recommendation:All TB cases should be offered HIV testing.10.5 Screening for LTBIIndividuals with symptoms of TB should have a chest X-ray and clinical evaluation as soon as possible,regardless of the TST result. Asymptomatic HIV-infected cases should have a TST (Mantoux test), an IGRA(if available) and chest X-ray to investigate the possibility that the patient has active disease. HIV positiveindividuals with an induration of >5mm and no chest X-ray findings are eligible for treatment of latentinfection.A baseline chest X-ray should be taken when a HIV diagnosis is confirmed, 360 and this committeerecommends that screening by chest X-ray should be undertaken every two to three years thereafter, todetermine any changes. CDC suggests annual repeat testing for those TST negative on initial testing andwho belong to a population at substantial risk of exposure. Furthermore, hepatitis C screening should alsobe considered, particularly for HIV-infected cases with a history of injecting drug use.Tuberculin skin testingThe prevalence of positive TSTs decreases progressively with declining CD4 count, 361 therefore the TST haslimited diagnostic value among patients with severe immunodeficiency. 34 The proportion of cases reactingto PPD declines from 50-90% for cases with a CD4 count of ≥ 500 cells/μl, to 0-20% for cases with a CD4count of ≤ 200 cells/μl. 345 Tuberculin reactivity tends to be lost because increasing immunodeficiencyresults in a weakened delayed-type hypersensitivity response to mycobacterial antigens. HAART (HighlyActive Antiretroviral Therapy) may improve the immune response to TB but patients most likely to go froma negative to a positive TST result are those whose CD4 rises by > 200 cells/μl. 345In the UK, BHIVA do not recommend tuberculin skin testing in patients with CD4 counts < 400 cells/μl, 345while CDC guidance indicates that TSTs are positive in the majority of patients with pulmonary disease andCD4+ T lymphocyte count > 200 cells/ul. The view of this committee is that a TST should be undertakenregardless of CD4+ T lymphocyte count, with the proviso that the result may be unreliable in an individualwith lower CD4 counts. TST indurations of >5mm should be considered positive regardless of BCG status,and evaluation and treatment of latent infection should be considered. Previous BCG vaccination in a HIVinfectedindividual does not infer immunity.Interferon gamma release assays (IGRA)The use of interferon gamma release assay for diagnosing latent and active TB has been addressedelsewhere in these guidelines (chapter 2). Despite being an immunological assay, studies suggest it maybe more useful for diagnosing LTBI in HIV-infected individuals than the tuberculin skin test. 34;362 However,further studies are required to correlate IGRA results with CD4 counts and to test the reproducibility of thetest in this population. 345 The lack of evidence concerning the utility of an IGRA in this population makes itdifficult to devise recommendations.It is recommended that the TST should be used initially to detect LTBI and a person with a positiveresult should be considered to have LTBI. 30 False negative results are not uncommon in immunodeficientindividuals; therefore if a clinician is concerned about the possibility of such a TST result, an IGRA canbe conducted. LTBI can be considered if an IGRA test is positive, while indeterminate results should be-126-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCrepeated. Indeterminate results may indicate laboratory error or anergy, therefore a person’s history, clinicalfeatures and laboratory findings must be taken into account when diagnosing LTBI using an IGRA.Diagnosis in childrenA high index of suspicion is required for TB in HIV infected children, as those under two years of age are atrisk of disseminated disease causing miliary TB or TB meningitis. It is advised therefore, that HIV infectedchildren are screened annually for TB, beginning at age three to 12 months. 217Diagnosis of TB can be complicated by failure to detect M. tuberculosis in gastric washings, pre-existenceor coincidental fever, pulmonary symptoms and chest X-ray abnormalities. 343 Cervical lymph nodesare commonly involved in extra-pulmonary cases. In children, lymphoid interstitial pneumonitis (LIP) isoften associated with persistent generalised lymphadenopathy (PGL), a feature of HIV infection. It canbe confused with TB as chronic symptoms are common. Lymphadenopathy due to LIP is generalised,symmetrical, mobile, non-tender, firm and non-fluctuant. Further information is available from the WHO’sguidelines for clinical management of TB/HIV. 344 (www.who.int/tb/hiv/en/).Recommendation:In HIV-infected individuals, routine screening for TB is advisable. HIV-infected children shouldbe screened annually for TB, beginning at age three to 12 months.10.6 Treatment of Active DiseaseThe standard treatment regimen for adult TB/HIV- infected persons is the same as for non HIV- infectedTB cases. It is recommended that physicians with appropriate expertise should be consulted prior to theinitiation of treatment, due to the complexity of co-administration of anti-TB and antiretroviral therapies.Treatment of TB/HIV infected childrenIn children aged less than five years, treatment should commence as soon as possible to avoiddissemination of disease. As with adults, the initial phase of treatment should involve a four drug treatmentregimen. Ethionamide can be used instead of ethambutol where TB meningitis is indicated, as it penetratesthe CNS more effectively. For HIV-infected children with active pulmonary disease, treatment durationshould be nine months and 12 months for extrapulmonary TB.10.7 Treatment of LTBI in HIV-Positive IndividualsTreatment of LTBI has been proven efficacious in HIV-infected individuals. 363-365 The optimal treatmentregimen for LTBI in HIV-infected persons of all ages is isoniazid for nine months or rifampicin and isoniazidfor four months, once medical evaluation has ruled out active TB disease. However, six months treatmentmay be realistic and easier to enforce. These recommended regimens are based on a review of theevidence and guidance in the international literature and by consensus of the National TB AdvisoryCommittee. Pyridoxine should also be administered to those in receipt of isoniazid to reduce the risk ofperipheral neuropathy (chapter 3). Antiretroviral therapy can be delayed until LTBI treatment is completed.Recommendation:The recommended treatment regimens for LTBI in adults who are HIV positive are:(i) Isoniazid for an optimum duration of nine months or(ii) Rifampicin for four months or(iii) A combination of rifampicin and isoniazid for four months.-127-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTreatment of LTBI in HIV-positive childrenFor exposed contacts with impaired immunity i.e. with HIV infection and for all contacts younger than fiveyears of age, isoniazid therapy should be initiated, even if the TST result is negative, once TB disease isexcluded.Recommendation:The recommended treatment regimens for LTBI in children who are HIV positive are:(i) Isoniazid for a minimum of six months with an optimum duration of nine months or(ii) Rifampicin for six months or(iii) A combination of rifampicin and isoniazid for four months.As there is significant potential for an interaction between rifampicin and antiretroviral agents it isimportant that treatment of LTBI in HIV positive children be undertaken by a specialist both in TB and HIV.Directly observed therapy (DOT)During the 1990s, the United States experienced a resurgence in TB because of immigration, a failingpublic health infrastructure and due to the emerging HIV epidemic. In New York, case notifications tripledand the proportion of drug-resistant isolates more than doubled between 1978 and 1992. To tackle thisgrowing problem, the programme of supervised medication taking was expanded. Improved rates oftreatment completion and decreasing case numbers were observed, giving credence to the concept ofdirectly observed therapy (DOT). 366-368 CDC and WHO advocate the use of DOT for HIV-positive individualsin receipt of a multiple TB drug regimen, due to the severity of the disease in immunodeficient persons. 369It is recommended that all TB/HIV patients should receive daily TB therapy. However, TB treatment maybe given five days a week by directly observed therapy. 345 Indications for intermittent therapy are thesame for HIV-infected and non HIV-infected patients. Thrice-weekly administration of a modified dose oftreatment can be used, particularly after daily administration during the initiation phase of treatment (firsttwo months). However, certain alternative regimens (once weekly isoniazid-rifapentine in the continuationphase, and twice weekly isoniazid-rifampicin/rifabutin in any HIV patient with CD4 count < 100 cells/ul)have been associated with the acquisition of rifampicin resistance and should be avoided. 345 <strong>Guidelines</strong> formanaging treatment and interruptions to treatment are provided in the BHIVA guidelines (www.bhiva.org/).Recommendation:Directly observed therapy (DOT) is recommended for treatment of all HIV-infected TB cases.10.8 Evaluation of a TB/HIV CaseBaseline evaluationThe BHIVA guidelines recommend that the following baseline measurements are made: 3451. Absolute CD4 count and percentage2. Measure LFTs, i.e. serum aminotransferases (AST, ALT), bilirubin and alkaline phosphatase. LFTsshould be retested at one to two weeks if asymptomatic3. Serum creatinine and a platelet count4. Serological testing for hepatitis B and C5. Visual acuity with Snellen charts when ethambutol is to be used6. A repeat smear and culture should be done after two months of treatment in a pulmonary TBpatient who still has a productive cough7. Chest X-ray if progress is unsatisfactory after two months. For patients with pulmonary TB,baseline and ‘completion of treatment’ chest X-rays are necessary and8. Other evaluations e.g. additional chest X-rays, ultrasound or CT scans may beindicated depending on the clinical need.-128-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC230BFollow up evaluationA clinical evaluation should be performed monthly to assess medication intolerance and adherence in TB/HIV-infected individuals. Treatment effectiveness should be monitored throughout the treatment period. Inpulmonary TB/HIV patients, a minimum of one sputum specimen should be examined microscopically eachmonth, until two consecutive specimens are negative on culture. Drug susceptibility should be re-evaluatedin patients with culture positive specimens after three months of treatment. The ease of monitoringtreatment effectiveness will be determined by the site of infection in extrapulmonary cases. More frequentmonitoring is required for patients with underlying liver disease including hepatitis C.The risk of relapse is believed to be the same in HIV-infected and non-infected TB cases receivingrifampicin for a minimum of six months. HAART has been shown to reduce the risk of relapse. 370-372Commencement of HAARTThe International Standards for TB Care 25 propose that all patients with TB/HIV co-infection should beevaluated to determine if antiretroviral therapy is indicated during the course of TB treatment. The useof co-trimoxazole in TB/HIV-infected individuals as prophylaxis against other infections should also beevaluated.While initiation of TB treatment should not be delayed, there is no international agreement on the optimaltime to start HAART in TB/HIV patients. Case-by-case assessments are made in an attempt to balancethe risk of progression of HIV against that of having to interrupt/discontinue therapies due to toxicities,side effects, drug interactions, etc. Delaying antiretroviral therapy can simplify patient management, limitadverse events, drug interactions and immune restoration reactions. Furthermore, studies have showndeaths due to TB are more common in the first month of TB treatment, while deaths occurring later onmay be due to HIV disease progression. 373-375 BHIVA recommend the following start times of antiretroviraltherapy in TB/HIV-infected patients.Table 10.1: Recommended HAART starting times (adapted from BHIVA guidelines)CD4 cells/μLCommencement of HAART200®After completing 6 months of TB treatment12F® CD4 count monitoring should be performed every 6-8 weeks. If CD4 count falls, patient may need to start HAART.The initiation of HAART within two to four weeks of anti-tuberculous therapy has been associated withdecreased HIV-1 progression (CDC) but a high incidence of adverse events and paradoxical reactions (seebelow). By delaying HAART by a minimum of four to eight weeks after initiation of TB therapy, specificcauses can be assigned to drug side effects and the severity of a paradoxical reaction can be reduced.Optimal timing for starting HAART should be based on an individual’s initial response to treatment, sideeffects and acceptance of antiretroviral treatment. 342TB treatment should only be modified when a patient has developed intolerance to, or severe toxicityfrom, HIV drugs or has evidence of genotypic resistance to specific HIV drugs thus limiting HAART therapyto agents which are likely to interact with anti-TB therapy. These factors may require the duration of TBtreatment to be extended. 345Factors complicating the treatment of TB/HIV 344;345Adverse pharmacological interactions occur between rifampicin and antiretroviral drugs used in thetreatment of HIV disease due to shared routes of metabolism. Due to these complexities of treatment, it isimportant that the use of both HAART and anti-TB treatment is managed by those with relevant expertise.Here we provide an overview of the complexities of concomitant treatment of HIV and TB.Rifampicin induces an enzyme in the hepatic cytochrome P-450 (CYP) system which is involved in themetabolism of protease inhibitors (PIs) and non-nucleoside reverse inhibitors (NNRTI). Rifampicin canaccelerate clearance of PIs and NNRTIs metabolised by the liver, resulting in sub-therapeutic levels of the-129-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCdrugs. Clinically important drug interactions can become evident after two weeks of treatment when theinducing effect is maximised and can persist for two weeks after rifampicin has been withdrawn from thetreatment regimen. Furthermore, rifampicin can enhance the activity that results in the elimination of PIsfrom the body. Despite these interactions, rifampicin should not normally be excluded from the standardtreatment regimen for TB/HIV cases receiving antiretroviral therapy.An immune reconstitution inflammation syndrome (IRIS) or a paradoxical reaction is a temporaryexacerbation of TB symptoms or radiographic findings after beginning anti-TB treatment. It has beendescribed in non HIV-infected individuals but is more common in HIV positive cases. It occurs because ofreconstitution of immune responsiveness due to HIV or TB treatment which leads to an abnormal immuneresponse to TB antigens released by dead/dying bacilli and is accompanied by a high fever, increasedsize and inflammation of lymph nodes, new lymphadenopathy, expanding CNS lesions, worsening oflung parenchymal infiltrations and pleural effusions. Management of a non-severe paradoxical reactioninvolves treatment of symptoms with non-steroidal anti-inflammatory agents. Some studies have shownthat more severe reactions involving high fever, airway compromise by enlarging lymph nodes, enlargingserosal fluid collections and sepsis syndrome can be treated with prednisone or methylprednisolone.IRIS can be transient, yet last for many months. Most cases experiencing IRIS are at an advanced stageof immunodeficiency. Patients commenced on HAART within the first two months of TB treatment are atgreater risk of IRIS.Overlapping toxicity profiles also occur in individuals receiving concomitant treatment for HIV and TB.NNRTIs and co-trimoxazole, and rifampicin, isoniazid and pyrazinamide used to treat TB are all associatedwith side effects of fever, rash, peripheral neuropathy and other neurological events, gastrointestinalintolerance and hepatitis. Side effects are most common in the first two months of treatment.Dispensing of HIV and anti-TB therapyGiven the complex drug interactions that can occur between HIV and anti-TB medications, and the needto be able to monitor compliance, patients receiving therapy for both HIV and TB or LTBI should receivetheir HIV and TB medications from the same pharmacy, from a pharmacist experienced in the use of thesemedications. The pharmacist should keep records of TB and HIV medications dispensed to each patientand advise patients on the importance of compliance with their treatment and on potential adverse drugreactions and interactions. Pharmacists should also be part of the multidisciplinary team looking afterpatients with TB/HIV infection. They have an important role in the provision of advice on dosages for anti-TB and HIV medications, on therapeutic drug monitoring for patients who are receiving treatment withdrugs such as amikacin and in monitoring the patient for adverse drug reactions e.g. hepatotoxicity.10.9 Prevention and ControlCases of TB in HIV positive individuals should be notified and contact tracing undertaken as recommendedfor non-HIV infected TB cases (chapter 8).HIV positive cases are not considered to be more infectious to their contacts than HIV negativeindividuals. 376;377 On the contrary, it has even been suggested that the likelihood of transmission is reducedbecause bacillary loads are lower and cavitary disease is less common than in non-HIV infected TB cases.However, this has not been proven on an individual case basis, and procedures for contact tracing andinfection control measures should be applied in the same manner as for non-HIV infectious TB cases.HIV infection does lead to a greater likelihood of TB infection progressing to active disease and a highproportion of infections in this population result in disease with a short time frame between exposure andthe development of symptoms.BCGThere is international agreement that BCG is contraindicated in HIV positive individuals. 26;52;369 In countrieswhere the risk of TB is low, it is recommended that BCG should be withheld from all individuals known orsuspected to be HIV positive. 26 Infants born to known HIV positive women should have BCG deferred untilafter the second HIV PCR proves negative (usually at/after 6 weeks of age). 332 The benefit of vaccinatingHIV-infected individuals to prevent the development of TB is as yet unproven, 378 and adverse events-130-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCrelating to complications from BCG e.g. ulceration, regional lymphadenopathy and dissemination have255, 257been reported.Infection prevention and control (see chapter 6)Hospital management of a HIV-TB case should include single room accommodation for a pulmonary case,preferably with negative pressure ventilation. HIV positive or other immunosuppressed individuals shouldnot be exposed to possible or confirmed infectious cases. 379 Aerosol-producing procedures should beconducted in isolation rooms with sufficient ventilation to ensure airborne particles are removed betweeneach patient’s use. Furthermore, exposure to HCWs should be minimised by reducing the number ofworkers involved in direct care, e.g. using a named-nurse system/primary nursing. Individual assessmentsshould be made with regards to risks for visitors.-131-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC11. Education, Research and Information11.1 EducationThe increased rates of TB in Ireland over the last seven years demand better education of our medical,nursing and pharmacy personnel about this important disease. Our public health priorities include suchissues as dealing with LTBI in at-risk populations, TB disease prevention and treatment in immigrants andmultiple drug-resistant TB disease. The small amount of time invested in TB education of Irish HCWs leavesthem poorly prepared to address these emerging challenges.Recommendation:Given the increased importance of LTBI and TB diagnosis and treatment, TB education in theundergraduate and postgraduate medical/nursing disciplines needs to be strengthened.11.2 ResearchResearch into TB has progressed apace, since the publication of the last national TB guidelines, 113 with newdrug options, and new tests that seek to address resistant TB and difficult to diagnose TB disease. In thisregard, a diarylquinoline anti-TB drug is under development, 380 and the IGRA blood tests have become amainstream option to diagnose LTBI. 57 IGRA on pleural fluid and bronchoscopy washings are also understudy. 381 Meanwhile, basic research has improved our understanding of the host response to TB andallowed new vaccine designs that may improve on BCG. 382 Finally, our understanding of the host responsehas allowed us predict and prevent reactivation of TB in patients taking specific cytokine blockers whichmake these immunosuppressants safer. 93A number of researchers in TB have relocated to Ireland and they are collaborating with immunologists,epidemiologists and scientists with an interest in bovine TB. Such work will inform better treatment, testsand vaccine design. It is noted however, that we specifically lack any data on LTBI prevalence and also onthe use of IGRA in the diagnosis of LTBI in the Irish population.In contrast to other diseases, TB research often lacks industry sponsorship. We therefore encouragecontinued research funding of this neglected disease by our governmental funding agencies. Researchfellows willing to undertake TB research should be fostered and given seed money to try and promote suchactivity. The challenge falls to us to encourage our brightest investigators into the field of TB research.The development of the IGRA blood tests for LTBI, the development of immunotherapies to treat multipledrug-resistant TB cases and the advances in vaccinology makes the TB field a scientifically exciting one topursue. A number of worldwide consortia have been established to investigate TB (e.g. TBNET), and it isencouraged that Irish investigators should join such consortia to deliver answers to important questionsthat require a large number of patients (e.g. MDR-TB or XDR-TB treatment regimen development).Recommendation:Research that seeks to improve our understanding of the pathobiology of tuberculosis aswell as the nature of the disease in our own country is to be encouraged; research fundingagencies should foster such activity, which has the potential to improve the treatment of thedisease both locally and internationally.Studies to determine the prevalence rate of LTBI should be initiated and supported.-132-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC11.3 InformationEven as we see the deterioration of the general level of TB knowledge amongst our healthcare workers,it is important that we address this trend through specific information and research centred events. Thisdocument will help this process, however, it should be supported with publications and articles in themedical journals and medical literature as well. A formal annual TB meeting might serve as a focus pointfor this activity. Where possible, members of this committee should be available to provide a balanced andinformed view of the disease when called upon by television, radio and/or public newspapers.-133-

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<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC(364) Moreno S, Miralles P, Diaz MD, Baraia J, Padilla B, Berenguer J et al. Isoniazid preventive therapy inhuman immunodeficiency virus-infected persons. Long-term effect on development of tuberculosisand survival. Archives of Internal Medicine 1997; 157:1729-1734.(365) Whalen CC, Johnson JL, Okwera A, Hom DL, Huebner R, Mugyenyi P et al. A trial of three regimensto prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. NewEngland Journal of Medicine 1997; 337:80180-808.(366) Brudney K, Dobkin J. Resurgent tuberculosis in New York City: human immunodeficiency virus,homelessness, and the decline of tuberculosis control programs. American Review of RespiratoryDisease 1991; 144:745-749.(367) Centers for Disease Control and Prevention. Emerging infectious diseases. Tuberculosis morbidity -United States 1992. Morbidity and Mortality Weekly Report 1993; 42:696.(368) Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City- turning the tide.New England Journal of Medicine 2007; 333:229-233.(369) Centers for Disease Control and Prevention. <strong>Guidelines</strong> for preventing opportunistic infectionsamong HIV-infected persons - 2002. Morbidity and Mortality Weekly Report 2002; 51(RR-8):1-17.(370) Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosisin South Africa: a cohort study. Lancet 2002; 359:2059-2064.(371) Jones BE, Young SM, Antoniskis D, Davidson PT, Barnes PF. Relationship of the manifestations oftuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. AmericanReview of Respiratory Disease 1993; 148:1292-1297.(372) Santoro-Lopes G, de Pinho AM, Harrison LH, Schecter GF. Reduced risk of tuberculosis amongBrazilian patients with advanced human immunodeficiency virus infection treated with highly activeantiretroviral therapy. Clinical Infectious Diseases 2002; 34:543-546.(373) Churchyard GJ, Kleinschmidt I, Corbett EL, Murray J, Smit J, De Cock KM. Factors associated withan increased case-fatality rate in HIV-infected and non-infected South African gold miners withpulmonary tuberculosis. International Journal of Tuberculosis and Lung Disease 2000; 4:705-712.(374) Murray J, Sonnenberg P, Shearer SC, Godfrey-Fausset P. Human immunodeficiency virus and theoutcome of treatment for new and recurrent pulmonary tuberculosis in African patients. AmericanJournal of Critical Care Medicine 1999; 159:733-740.(375) Nunn P, Brindle R, Carpenter L, Odhiambo J, Wasunna K, Newnham R et al. Cohort of humanimmunodeficiency virus infection in patients with tuberculosis in Nairobi, Kenya: analysis of early(6-month) mortality. American Review of Respiratory Disease 1992; 146:849-854.(376) Carvalho AC, DeRiemer K, Nunes ZB, Martins M, Comelli M, Marinoni A et al. Transmission ofMycobacterium tuberculosis to contacts of HIV-infected tuberculosis patients. American Journal ofRespiratory and Critical Care Medicine 2001; 164(12):2166-2171.(377) Cruciani M, Malena M, Bosco O, Gatti G, Serpelloni G. The impact of human immunodeficiencyvirus type 1 on infectiousness of tuberculosis: a meta-analysis. Clinical Infectious Diseases 2001;33(11):1922-1930.(378) Iseman D. Tuberculosis in relation to HIV and AIDS. A clinician’s guide to tuberculosis. Philadelphia:Lipincott Williams and Wilkins; 2000. 199-252.(379) The interdepartmental Working Group on Tuberculosis. The prevention and control of tuberculosisin the United Kingdom: UK guidance on the prevention and control of: 1 HIV-1 related tuberculosis;2 drug resistant including multiple drug-resistant tuberculosis. 1998. Department of Health, UK.(380) Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H et al. A diarylquinolinedrug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307(5707):223-227.-154-

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<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCList of AppendicesAppendix 1:Appendix 2:Appendix 3:Appendix 4:Appendix 5:Appendix 6:Appendix 7:Appendix 8:Appendix 9:List of Groups who were ConsultedNotification Pathway for a Case of TBTuberculosis Notification FormWays to Assess and Promote Adherence to LTBI TreatmentTB Therapy Audit FormQuestions and Answers about TBContact Details for Clinical and Laboratory TB AdviceInternational Standards for TB CareDOT Referral form-HSE South (Cork and Kerry)Appendix 10: Standard and Airborne PrecautionsAppendix 11: Discharge Instructions for Patients with Potentially Infectious TBAppendix 12: List of TB-related Websites and ResourcesAppendix 13: Respiratory Hygiene and Cough Etiquette-156-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 1: List of groups who were consultedThe following is a list of those to whom a draft of the document was sent for consultation as well as thosewho made submissions. The document was also posted on the HPSC website. We would like to thankthose who made submissions for their invaluable contribution to this document.Academy of Medical Laboratory ScienceClaire Keane, Senior Pharmacist, St. Vincent’s University Hospital, Elm Park, Dublin 4Consultants in Public Health MedicineDirectors of Public HealthDirectors of Public Health Nursing in HSE areasDr Eibhlin Connolly, Deputy Chief Medical Officer, Department of Health and ChildrenDr Karoline de La Hoz, European Centre for Disease Prevention and ControlDr Enda Dooley, Medical Director, Department of Justice, Equality and Law ReformDr Pat Doorley, National Director of Population HealthDr Kevin Kelleher, Assistant National Director of Health ProtectionDr Jim Kiely, Chief Medical Officer, Department of Health and ChildrenDr Tom O Connell, Chief Medical Officer, Occupational Health Department, Civil ServiceEmergency Medicine AssociationFaculty of Occupational Medicine, Royal College of Physicians of IrelandFaculty of Paediatrics, Royal College of Physicians of IrelandFaculty of Pathology, Royal College of Physicians of IrelandFaculty of Public Health Medicine, Royal College of Physicians of IrelandFaculty of Radiology, Royal College of Surgeons of IrelandGeraldine O Connell Public Health Nurse, South Lee Public Health Nursing DepartmentImelda O Connor, Public Health Nurse, HSE-MidwestIrish College of General PractitionersIrish Infection SocietyInfection Prevention SocietyIrish Medicines BoardIrish Society of Clinical MicrobiologistsIrish Society of GastroenterologyIrish Society of Physicians in Geriatric MedicineIrish Society of RheumatologyIrish Thoracic SocietyMaeve Moran, Senior Pharmacist, St. Vincent’s University Hospital, Elm Park, Dublin 4Mairead Lane, Occupational Health Department, Mid-Western Regional Hospital, Limerick,Marie Philbin, Chair of Irish Antimicrobial Pharmacists GroupNational Immunisation Advisory Committee, Royal College of Physicians of IrelandNational Immunisation OfficePrincipal Medical Officers, HSEPublic Health Medicine Communicable Disease GroupRoyal College of Physicians of IrelandSchool of Pharmacy, Royal College of Surgeons, IrelandStella Sheehan, Senior Medical Laboratory Technician, Cork University HospitalSurveillance Scientists AssociationThe Federation of Irish Nursing Homes-157-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 2: Notification pathway for a case of TBCase of TB(GP, respiratory/infectious diseaseclinician, nursing home, laboratory, etc)Notify the department of publichealth (DPH/MOH) in relevantHSE areaWeekly notifications once TB isincorporated onto CIDRCurrently NTBSS 2000 quarterlyreturnsHealth ProtectionSurveillance CentreQuarterly and annual nationalTB reportsTB is a notifiable disease. A case of TB should be notified to the department of public health in the relevant HSEarea. Currently, the department of public health in turn notifies HPSC through the enhanced TB surveillancesystem each quarter. Once TB is incorporated onto CIDR, TB cases will be notified to HPSC in “real-time”/weekly basis. HPSC produces quarterly and annual national TB reports.-158-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 3: Tuberculosis Notification FormNational Tuberculosis Notification FormTB Case Registration: Health AreaCountyCCAYear 2 0Sequence NumberFirst Name / InitialSurname / InitialAddressPhoneA. SOCIODEMOGRAPHIC DETAILS B. DIAGNOSTIC & CLINICAL DETAILS1. Sex: Male Female2. Date of Birth3. Age (years)4. Most recent occupation5. Current employment statusPaid employmentUnemployedRetiredStudentHousewife / husbandOtherIf OTHER, please specify:6. Current living statusHome (private / rented) InstitutionB&B / HotelHostelHomelessPrisonOther If OTHER, please specify:7. Country of BirthIrelandOtherIf OTHER, please specify country:8. Race or ethnic groupCaucasianTravellerBlackChineseIndian subcontinent OtherIf OTHER, please specify:9. Refugee / asylum seekerYes NoIf YES, date/year of entry into Ireland:10. Date of onset of symptoms11. Date diagnosed12. Date of notification13. Diagnosis (tick one only)If Extrapulmonary or P+E,please specify site(s)15. Histology:PulmonaryPositiveNot done16. Chest x-ray:Active TBNormalNegativeUnknownInactive / Old TBOtherExtrapulmonaryPulmonary + extrapulmonary (P+E)14. Direct sputum microscopy:(a) 1st specimenSpecimen date(b) 2nd specimenSpecimen dateZN posZN negZN not doneZN posZN negZN not done17. Culture ResultsCulture posCulture negCulture not done UnknownIf done, please specify culture site:18. IsolateM. TBM. BovisOtherUnknownIf OTHER, please specify:19. Drug sensitivities(S = sens, R= res, N = not done)(Please fill for each drug used)IsoniazidPyrazinamideOther (specify)20. This case was found byPresenting as caseImmigrant screeningOther (specify)21. Previous history of TBYes NoIf YES, please specify:(a) year of diagnosis(b) treated >1month?Yes No(c) cured?Yes No22. BCG GivenYes23. BCG ScarYes24. Risk FactorsYesNoNoNo25. Immune Code(see explanatory notes)RifampicinEthambutolContact tracingOther screeningUnknownUnknownUnknownUnknownUnknownUnknownIf YES, please specify:(e.g. immunosupression, C2H5xs, IVDU)C. OUTCOME DETAILS (**Please note that 26 (a), (b), (c) and (d) apply to SMEAR POSITIVE cases ONLY**)26. (a) At 2 mths:Direct Sputum microscopyZN posZN negZN not doneCulturePosNegNot doneIf ZN pos at 2 mths then go to (b), otherwise go to (d)(b) At 3 mths:Direct Sputum microscopyZN posZN negZN not doneCulturePosNegNot doneIf ZN pos at 3 mths then go to (c), otherwise go to (d)(c) At 5 mths:Direct Sputum microscopyZN posZN negZN not doneCulturePosNegNot donePlease now go to (d)(d) Rx end:Direct Sputum microscopyZN posZN negZN not doneCulturePosNegNot done27. Treatment OutcomeCompletedInterrupted (>2months)Lost to follow up DiedIf dead, date of deathIf dead, was TB the direct cause?YesNo28. Case Denotified? (i.e. was diagnosis changed?)Yes NoIf YES, please specify new diagnosis-159-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC(D) CASE LOCATION DETAILSNational Tuberculosis Notification FormDED name / code:Hospital name:Chart Number:Work Address:School Address:(E) CONTACT TRACING DETAILSIs this case:Index case or Contact of another case (please tick 1)If contact of another case, please completeName of index case:Address ofindex case:REG ID of index case:Date of notification of index case:COMPLETING DOCTOR SIGNATURETick section(s) completed:Signature 1Date 1Section completed:ABCDESignature 2Date 2Section completed:ABCDESignature 3Date 3Section completed:ABCDESignature 4Date 4Section completed:ABCDESignature 5Date 5Section completed:ABCDESignature 6Date 6Section completed:ABCDEThank you for completing this form.Please forward completed forms to your local Department of Public Health-160-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 4: Ways to assess and promote adherence to LTBItreatmentWays to assess and promote adherence to LTBI treatment1. Use directly observed therapy (DOT) for LTBI when available especially for foreign-born personsfrom countries with an annual TB notification rate ≥ 40 cases per 100,000, homeless persons andintravenous drug users2. Provide written information about the potential adverse effects of the medications at the start oftreatment3. Send reminder letters or call patients before appointments4. Follow up promptly on missed appointments to prevent interruption or cessation of treatment5. Minimise wait time at clinics6. Ask patients at monthly visits about the number of missed pills in the past week7. Remind patients to bring in their medication bottle (s) and monitor pill counts (but not in theirpresence)8. During each monthly visit, stress the importance of adherence and educate patients about thepotential adverse effects of medication.Adapted with kind permission from Tuberculosis, Clinical Policies and Protocols. New York City Departmentof Health and Mental Hygiene (2008). Available from www.nyc.gov/html/doh/downloads/pdf/tb/tbprotocol.pdf.-161-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 5: Tuberculosis Therapy Audit FormTuberculosis Therapy Audit FormPreventive and Curative Therapy MonitorSurnameAddressPhoneHSE areaLHOForenameDOBHospital/clinicAge (years)Is the patient a: TB case TB contact Date therapy startedIndex case numberContact numberIndex case details - TB diagnosis: Clinically suspectedLaboratory confirmedSite:PulmonaryExtrapulmonarySputum smear: PositiveNegativeMonth 1 - 6DateTREATMENTIsoniazidRifampicinPyrazinamideStreptomycinEthambutolOther (please specify)COMPLIANCEAdministration (S or D)*SYMPTOM CHECKAnorexiaNauseaVomitingAbdominal discomfortRashJaundiceDark urineFever (> 3 days)Fatigue (> 3 days)ParaesthesiaOther (please specify)INVESTIGATIONSLFTs done? (Y/N)Alk Phos (result)ALT / SGPTAST / SGOTGGTBilirubin (total)Bilirubin (direct)Sputum sample (Y/N)Direct micro (Y/N)Culture (Pos/Neg)Resistance (Y/N)If Resistant, specify1 234 567YES= NO=GOOD = +++, UNCERTAIN = ++, UNSATISFACTORY = +Record result once available. Not available =* S = Self administered, D = Directly Observed (Preventive) Therapy i.e. DOT-162-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 6: Questions and Answers about TuberculosisWhat is Tuberculosis?Tuberculosis or “TB” is a disease caused by a bacterium (germ) called Mycobacterium tuberculosis. TBusually affects the lungs but it can also affect other parts of the body, including the glands, the bones andrarely the brain.Tuberculosis used to be more common in Ireland. There were nearly 7,000 cases a year in the early 1950s.The incidence of TB has declined steadily since then. In 2006, there were 465 cases notified in Ireland.Doctors are obliged to notify each case of TB to the local departments of public health in the HealthService Executive.TB disease is preventable and curable.What are the symptoms of TB?Symptoms of TB can include any of the following:• Fever and night sweats• Cough (generally lasting more than 3 weeks)• Weight loss• Blood in the sputum (phlegm) at any time.A person with any of these symptoms should visit their family doctor for advice.How is TB spread?TB is usually spread in the air from another person who has TB of the lungs. It is spread by that personcoughing, sneezing or spitting. People with TB in the lungs or throat can be infectious. This means that thebacteria can be spread to other people. Even then close and prolonged contact with such a person (i.e.family, friends, childminder, co-worker) is needed to become infected. Most cases of infectious TB stopbeing infectious after a few weeks of treatment. TB in other parts of the body such as the kidney or spine isusually not infectious.Another type of TB called Mycobacterium bovis can arise from drinking contaminated milk. This form of TBis now rare as pasteurisation of milk removes the risk.The following people have a greater chance of becoming ill with TB, if exposed to it:• Those in very close contact with infectious people• Children• Elderly people• Diabetics• People on steroids• People on other drugs affecting the body’s defence system• People who are HIV positive• People in overcrowded, poor housing• People dependent on drugs or alcohol• People with chronic poor health.What happens when a person is found to have infectious TB?• Treatment for TB is started• Public health doctors talk to the infected patient to see if other people need to be checked for TB.What is the difference between latent tuberculosis infection and active tuberculosis disease?Infection with the TB bacterium may not develop into TB disease. Most people who are exposed to TB are-163-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2009HSE/HPSCable to overcome the bacteria. The bacteria become inactive but they remain dormant in the body and canbecome active later. This is called latent TB infection (LTBI).People with LTBI:• Have no symptoms• Don’t feel sick• Can’t spread TB to others• Usually have a positive skin test reaction• Can develop TB disease later in life.Most people who have LTBI never develop active TB disease. In these people, the TB bacteria remaininactive for a lifetime without causing disease. But in other people, who have weak immune systems, thebacteria can become active and cause TB disease.The difference between latent TB infection and active TB diseaseA person with Latent TB Infection• Has no symptoms• Does not feel sick• Usually has a positive skin test orblood test• Has a normal chest X-ray andsputum testA person with Active TB Disease• Has symptoms which may include:A bad cough which lasts three weeks or longerPain in the chestCoughing up sputum (phlegm) or bloodWeakness or fatigueWeight lossNo appetiteChillsFeverNight sweats• May spread TB to others• Usually has a positive skin test or positive blood test• May have an abnormal chest X-ray or positive sputumsmearor cultureHow is TB diagnosed?There are a number of tests that can be done to check for TB:• A skin test• A chest X-ray• A test of the sputum (phlegm)• A blood or urine test.How is TB treated?Yes, today TB is potentially completely curable, if the responsible organism is fully sensitive to theantibiotics being used and the patient takes his or her medication as prescribed.TB is treated with tablets which must be taken for at least six months. Without treatment, many peopleused to die from TB. It is essential to take the treatment regularly and to complete the course asprescribed.The most common medicines used to treat TB are: isoniazid, rifampicin, ethambutol and pyrazinamide. Avitamin B6 tablet called pyridoxine is also prescribed to help prevent some of the side effects that may becaused by isoniazid. Your doctor will decide which TB drugs are best for you.-164-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2009HSE/HPSCIf you have infectious TB (TB disease of the lungs or throat), you will need to stay at home from work orschool so that you don’t spread the TB bacteria to other people. After taking your medicines for a fewweeks, you will feel better and will no longer be infectious to others. Your doctor will tell you when you canreturn to work or school or visit friends.What are the side effects of TB medicines?If you are taking medicines for TB, you should take them as directed by your doctor or nurse. Themedicines may cause side effects but everyone can react differently and not everyone will have sideeffects. It is important to report any side effects to your doctor even if they are not listed below. Sideeffects include:• No appetite• Nausea (feeling sick in the stomach) and/or vomiting• Abdominal pain (tummy pain)• Yellowish skin or eyes• Dark-coloured urine• Fever for 3 or more days• Skin rash• Itching• Tingling of fingers or toes or around the mouth• Easy bleeding and/or bruising• Blurred or changed vision• Ringing in the ears• Hearing loss• Dizziness• Aching joints.The following side effects are caused by rifampicin. If you have any of these side effects you can continueyour medications (your doctor will advise you of these before starting treatment for TB):Rifampicin can:• Turn your urine, saliva (spit) or tears orange. The doctor or nurse will advise you not to wearcontact lenses as they may get stained.• Make your skin more sensitive to the sun. This means you should use a good sunscreen and coverexposed areas so that they don’t burn.• Make birth control pills and implants less effective. Women who take rifampicin should use anotherform of birth control.How important is treatment?Treatment is very important. If you have TB disease or if you have been infected with the TB bacterium buthave not yet become unwell i.e. have LTBI, you must take the treatment as directed. It is very important tocomplete the full course of treatment as it will stop you being infectious (spreading the disease to others)and it will remove the risk of you developing drug-resistant TB. It is important to remember that TB used tokill people before we had modern treatments.Can I drink alcohol with my medication?It is always best to avoid alcohol while you are taking TB medicines. This is because drinking any alcoholcan increase the chances of having problems with your liver when taking the medications.What precautions need to be taken to prevent TB spreading in the home?Some patients who are infectious (with TB) can remain at home in the household that has already beenexposed. However, the following precautions should be taken:• Use tissues when sneezing or coughing and place into a household bin immediately after use• Wash hands after disposing of the tissues• Stay at home and do not go to places where there will be previously unexposed people (e.g. pubs,clubs, cinemas)• Attend all outpatient visits• No visits by previously unexposed people-165-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSC• Children who do not live at home should not visit until your doctor allows• Relatives or friends who have weakened immune systems should not visit until your doctor allows• You can go for a walk outside but you should avoid close contact with previously unexposedpeople.Most people are no longer infectious when they have completed a few weeks of TB tablets and arefeeling better and their cough is gone or improving. However your doctor will advise you when the aboveprecautions are no longer necessary. It is also very important that you continue your medications until thedoctor tells you to stop.What should I do if I have been in contact with someone with TB?Discuss this with your family doctor. Only close contacts are at risk of catching TB. You may be asked toattend a chest clinic and to have a skin test and/or a chest X-ray. Sometimes a doctor or nurse will contactyou first (they will have a list of close contacts of the person who has TB). This does not necessarily meanthat you have TB but is a chance to check for it, so it is very important to attend if you are asked to.Can TB be prevented?Yes it can, in several ways:• Treating all people with active TB disease promptly. After two weeks of treatment, most patientsare no longer infectious to other people.• Ensuring that all close contacts of people with TB are seen promptly in the chest clinic. Thosefound to have LTBI or those at high risk of developing TB after close contact may be offered acourse of preventive therapy (chemoprophylaxis) once active TB has been ruled out.• Vaccination: In Ireland the BCG vaccination (vaccine against TB) is recommended for newbornbabies. BCG is also given to adults who are considered to be at risk of developing TB wherepotential contact with the disease could occur or has occurred. BCG vaccine is very effective,particularly in preventing childhood TB and the more severe forms of TB.What are multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB)Multidrug-resistant TB (MDR-TB)MDR-TB is a specific form of TB which is resistant to at least isoniazid and rifampicin, two of the main firstline drugs used in the treatment of TB. MDR-TB therefore is much more difficult to treat. It takes longer totreat with second line drugs which are more expensive and have more side-effects.Extensively drug-resistant TB (XDR-TB)XDR-TB is a rare type of MDR-TB which is also resistant to any of a group of drugs called fluoroquinolonesand at least one of three injectable second line anti-TB drugs (capreomycin, kanamycin or amikacin).Because XDR-TB is resistant to first line and second line drugs, treatment options are more limited.Further information on XDR-TB can be found on the WHO website at www.who.int/tb/challenges/xdr/en/index.htmlInformation on TB in Ireland can be found on the Health Protection Surveillance Centre website atwww.hpsc.ie/hpsc/A-Z/VaccinePreventable/TuberculosisTB/.-166-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 7: Contact details for clinical and laboratory TB adviceRespiratory PhysiciansDr Tim McDonnell, St Vincent’s University Hospital, DublinDr Brendan Keogh, Mater Misericordiae Hospital, DublinDr Terry O Connor, Mercy University Hospital, CorkDr JJ Gilmartin, University College Hospital, GalwayInfectious disease PhysiciansDr C. Fleming, University College Hospital, GalwayDr Karina Butler, Our Lady’s Hospital, Crumlin, DublinConsultant MicrobiologistsDr Margaret Hannan, Mater Misericordiae Hospital, DublinDr Bartley Cryan, Cork University HospitalIrish Mycobacteria Reference LaboratoryMr Noel Gibbons, Chief Medical Scientist, (01) 416 2963, ngibbons@stjames.ieProf T Rogers, Clinical Director, (01) 896 2131, rodgerstr@tcd.ieDr J Keane, Consultant Respiratory Physician, (01) 410 3920, jkeane@stjames.ieWebpage: www.stjames.ie/Departments/DepartmentsA-Z/I/IMRL/DepartmentOverview/or go to www.stjames.ie choose Lab services and then Irish Mycobacteria Reference LaboratoryAntimicrobial Reference Laboratory,Department of Medical Microbiology,North Bristol NHS Trust,Southmead Hospital,Bristol BS10 5NB,United KingdomThe Antimicrobial Reference Laboratory user manual may be found at www.bris.ac.uk/bcare/AssayBooklet.docResults and general inquiries: Tel. No: 00-44-117-959-5653Service EnquiriesProf A. P. MacGowan, Consultant Medical Microbiologist. Contact telephone no: 0044- 117-959-5652Email address: alasdair.macgowan@nbt.nhs.ukDr. A. M. Lovering, Consultant Clinical Scientist. Contact telephone no: 0044-117-959 5653Email address: andrew.lovering@nbt.nhs.ukMr. H. A. Holt, Laboratory Manager. Contact telephone no: 0044-117-959-5658Email address: alan.holt@nbt.nhs.uk-167-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 8: International Standards for Tuberculosis CareIn 2006 the “International Standards for Tuberculosis Care” were published to describe a widely acceptedlevel of care that all practitioners, public and private should seek to achieve in managing patients who haveor are suspected of having tuberculosis. The standards are outlined below. The full document is available atwww.who.int/tb/publications/2006/istc_report.pdf.Standards for DiagnosisStandard 1. All persons with otherwise unexplained productive cough lasting two to three weeks or moreshould be evaluated for tuberculosis.Standard 2. All patients (adults, adolescents, and children who are capable of producing sputum)suspected of having pulmonary tuberculosis should have at least two and preferably three, sputumspecimens obtained for microscopic examination. When possible, at least one early morning specimenshould be obtained.Standard 3. For all patients (adults, adolescents, and children) suspected of having extrapulmonarytuberculosis, appropriate specimens from the suspected sites of involvement should be obtained formicroscopy and, where facilities and resources are available, for culture and histopathological examination.Standard 4. All persons with chest radiographic findings suggestive of tuberculosis should have sputumspecimens submitted for microbiological examination.Standard 5. The diagnosis of sputum smear-negative pulmonary tuberculosis should be based on thefollowing criteria: at least three negative sputum smears (including at least one early morning specimen),chest radiography findings consistent with tuberculosis and lack of response to a trial of broad spectrumantimicrobial agents. (Note: Because the fluoroquinolones are active against M. tuberculosis complex andthus may cause transient improvement in persons with tuberculosis, they should be avoided.) For suchpatients, if facilities for culture are available, sputum cultures should be obtained. In persons with known orsuspected HIV infection, the diagnostic evaluation should be expedited.Standards for TreatmentStandard 6. The diagnosis of intrathoracic (i.e. pulmonary, pleural, and mediastinal orhilar lymph node) tuberculosis in symptomatic children with negative sputum smears should be based onthe finding of chest radiographic abnormalities consistent with tuberculosis and either a history of exposureto an infectious case or evidence of tuberculosis infection (positive TST or interferon gamma releaseassay). For such patients, if facilities for culture are available, sputum specimens should be obtained (byexpectoration, gastric washings, or induced sputum) for culture.Standard 7. Any practitioner treating a patient for tuberculosis is assuming an importantpublic health responsibility. To fulfill this responsibility the practitioner must not only prescribe anappropriate regimen but, also, be capable of assessing the adherence of the patient to the regimen andaddressing poor adherence when it occurs. By so doing, the provider will be able to ensure adherence tothe regimen until treatment is completed.Standard 8. All patients (including those with HIV infection) who have not been treatedpreviously should receive an internationally accepted first-line treatment regimen using drugs of knownbioavailability. The initial phase should consist of two months of isoniazid, rifampicin, pyrazinamide, andethambutol. The preferred continuation phase consists of isoniazid and rifampicin given for four months.Isoniazid and ethambutol given for six months is an alternative continuation phase regimen that may beused when adherence cannot be assessed, but it is associated with a higher rate of failure and-168-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCrelapse, especially in patients with HIV infection. The doses of antituberculosis drugs used should conformto international recommendations. Fixed-dose combinations of two (isoniazid and rifampicin), three(isoniazid, rifampicin, and pyrazinamide), and four (isoniazid, rifampicin, pyrazinamide, and ethambutol)drugs are highly recommended, especially when medication ingestion is not observed.Standard 9. To foster and assess adherence, a patient-centered approach to administration of drugtreatment, based on the patient’s needs and mutual respect between the patient and the provider, shouldbe developed for all patients. Supervision and support should be gender-sensitive and age-specific andshould draw on the full range of recommended interventions and available support services, includingpatient counselling and education. A central element of the patient-centered strategy is the use ofmeasures to assess and promote adherence to the treatment regimen and to address poor adherencewhen it occurs. These measures should be tailored to the individual patient’s circumstances and bemutually acceptable to the patient and the provider. Such measures may include direct observation ofmedication ingestion (directly observed therapy, DOT) by a treatment supporter who is acceptable andaccountable to the patient and to the health system.Standard 10. All patients should be monitored for response to therapy, best judged in patients withpulmonary tuberculosis by follow-up sputum microscopy (two specimens) at least at the time of completionof the initial phase of treatment (two months), at five months, and at the end of treatment. Patients whohave positive smears during the fifth month of treatment should be considered as treatment failuresand have therapy modified appropriately (see Standards 14 and 15). In patients with extrapulmonarytuberculosis and in children, the response to treatment is best assessed clinically. Follow-up radiographicexaminations are usually unnecessary and may be misleading.Standard 11. A written record of all medications given, bacteriologic response, and adverse reactionsshould be maintained for all patients.Standard 12. In areas with a high prevalence of HIV infection in the general population and wheretuberculosis and HIV infection are likely to co-exist, HIV counselling and testing is indicated for alltuberculosis patients as part of their routine management. In areas with lower prevalence rates of HIV, HIVcounselling and testing is indicated for tuberculosis patients with symptoms and/or signs of HIV-relatedconditions and in tuberculosis patients having a history suggestive of high risk of HIV exposure.Standard 13. All patients with tuberculosis and HIV infection should be evaluated to determineif antiretroviral therapy is indicated during the course of treatment for tuberculosis. Appropriatearrangements for access to antiretroviral drugs should be made for patients who meet indications fortreatment. Given the complexity of co-administration of antituberculosis treatment and antiretroviraltherapy, consultation with a physician who is expert in this area is recommended before initiation ofconcurrent treatment for tuberculosis and HIV infection, regardless of which disease appeared first.However, initiation of treatment for tuberculosis should not be delayed. Patients with tuberculosis and HIVinfection should also receive cotrimoxazole as prophylaxis for other infections.Standard 14. An assessment of the likelihood of drug resistance, based on history of prior treatment,exposure to a possible source case having drug-resistant organisms, and the community prevalence of drugresistance, should be obtained for all patients. Patients who fail treatment and chronic cases should alwaysbe assessed for possible drug resistance. For patients in whom drug resistance is considered to be likely,culture and drug susceptibility testing for isoniazid, rifampicin and ethambutol should be performedpromptly.Standard 15. Patients with tuberculosis caused by drug-resistant (especially multiple drug-resistant [MDR])organisms should be treated with specialised regimens containing second-line antituberculosis drugs.At least four drugs to which the organisms are known or presumed to be susceptible should be usedand treatment should be given for at least 18 months. Patient centered measures are required to ensureadherence. Consultation with a provider experienced in treatment of patients with MDR-tuberculosisshould be obtained.-169-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCStandards for Public Health ResponsibilitiesStandard 16. All providers of care for patients with tuberculosis should ensure that persons (especiallychildren under 5 years of age and persons with HIV infection) who are in close contact with patients whohave infectious tuberculosis are evaluated and managed in line with international recommendations.Children under 5 years of age and persons with HIV infection who have been in contact with an infectiouscase should be evaluated for both latent infection with M. tuberculosis and for active tuberculosis.Standard 17. All providers must report both new and retreatment tuberculosis cases andtheir treatment outcomes to local public health authorities, in conformance with applicable legalrequirements and policies.-170-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 9: DOT referral form-HSE South (Cork and Kerry)Hosp LogoAddressTO/ DIRECTOR OF PUBLIC HEALTH NURSINGREFERRAL REQUEST FOR DIRECTLY OBSERVED THERAPY(TUBERCULOSIS MEDICATION)North Lee □South Lee □North Cork □ West Cork □Kerry □Name ________________________________Home Address ___________________________________________________________________________________________________________________________________________D.O.B. __________________Current Address (if different) __________________________________________________________________________________________________________________________________________________Contact Number ________________________Hospital _______________________________Treating Consultant ______________________GP _______________________________Diagnosis ___________________________________________________________________Date of commencement of TB therapy _____________________________________________Most recent sputum: Date __________________ Result _________________________Case Currently Infectious? Yes □ No □ Mask wearing recommended? Yes □ No □(If yes, for how long? ___________________ )Reason/s for DOT Request?Poor/Non compliance Yes □ No □MDR-TB Yes □ No □TB Relapse Yes □ No □Homeless Yes □ No □Other Yes □ No □ (Specify:_____________________)Date Next OPD Appointment ______________________Patient informed of DOT Request? Yes □ No □TB Medication ________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________(Prescription faxed)Signed: _______________________________________________ Date ______________Referring Medical Consultant.□ c.c. Senior Medical Officer, Cork. Fax No. 021 4927370□ c.c. Senior Medical Officer, Kerry. Fax No. 066 7184542-171-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 10: Standard and Airborne PrecautionsStandard Precautions to be used by all HCWs for all patients in all settings at all timesandAirborne Precautions, in addition to Standard Precautions, should be instituted when caring for a suspected or confirmed case of infectious pulmonary or laryngealTBSee chapter 6 for definition of infectious caseSee chapter 6 for criteria for discontinuation of Airborne PrecautionsStandard Precautions must be continued for all patients once Airborne Precautions are discontinuedClinicalWorkPracticeSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSOccupationalHealthProgrammeAll HCWs should be assessed by an occupational heath team prior tocommencing work. This assessment should include:•Immunisations (Irish guidelines on immunisations requiredfor HCWs are available at www.hpsc.ie/hpsc/A-Z/VaccinePreventable/Vaccination/Guidance/)• Screening HCWs who perform exposure prone procedures forblood borne viruses. DoHC guidelines available at www.dohc.ie/publications/transmission_of_blood_borne_diseases_2006.htmlPatientPlacementHCWs should include the potential for transmission of infectiousagents in patient placement decisionsWhere possible, place patients who contaminate the environment orcannot maintain appropriate hygiene in isolation rooms with en suitetoilet facilities and ante roomPlace all patients with suspected or confirmed pulmonary or laryngeal TBin one the following airborne isolation rooms. Refer to figure 6.1 for riskassessment algorithm if an airborne isolation room is not available. Refer tosection 6.5 for engineering standards1.Negative pressure isolation room with a hand wash sink, an ante roomand en-suite2.A neutral pressure design room, as detailed in HBN 04 Supplement 1Patients with known or suspected multi drug-resistant TB (MDR-TB) mustbe placed in an airborne isolation room which may require transfer of thepatient to another facilityA notice should be placed on the door of the isolation room advising thoseentering to report to the nurse in charge before enteringPatients should be educated regarding the reason/indication for AirbornePrecautions and requested not to leave the room unless absolutely necessaryClinical STANDARD PRECAUTIONS AIRBORNE PRECAUTIONS-172-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticePatientPlacement(cont)ClinicalWorkPracticeHandHygieneentering to report to the nurse in charge before enteringPatients should be educated regarding the reason/indication for AirbornePrecautions and requested not to leave the room unless absolutely necessarySTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSHCWs should include the potential for transmission of infectiousagents in patient placement decisionsWhere possible, place patients who contaminate the environment orcannot maintain appropriate hygiene in isolation rooms with en suitetoilet facilities and ante roomEmergency departments (ED) without an airborne isolation room must have aprocess in place to prioritise transfer of patients with suspected or confirmedTB to an appropriate room. ED departments without any airborne isolationrooms should place a surgical mask on the patient and place him/her in anexamination room or single room while awaiting transfer. This room shouldbe left vacant for 1 hour once the patient is transferred to allow for a fullexchange of air.Aerosol-generating procedures such as sputum induction and theadministration of medications by nebuliser must be avoided while a patientwith suspected or confirmed TB is in an open bay or an unventilated area inany wardBronchoscopy should preferably be performed in an appropriate negativepressure suite with adequate ventilation. Unnecessary staff and other patientsshould be excluded during the procedure. If endoscopy rooms are without airhandling equipment, the procedure should be done at the end of the list forthe day, or in the patient’s room. Avoid placement of recovering patients in amulti-bedded ward post procedure.Procedures on an extrapulmonary TB open abscess or lesion whereaerosolisation of drainage fluid may occur should only be undertaken in anairborne isolation roomSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSHand hygiene is recommended;••••••Before and after each episode of patient contactBetween individual patient contactsAfter contact with blood, body fluids, secretions orexcretions, whether or not gloves are wornAfter handling soiled/contaminated equipment, materials orthe environmentImmediately before glove applicationImmediately after removing gloves or other protectiveclothingAntiseptic soap or alcohol gel if hands are physically clean before and afterpatient careHands should be decontaminated using soap and water or alcoholgel if physically clean. Antiseptic soap should be used prior toaseptic procedures.Patients should wash their hands after toileting and before meals.-173-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticeHandHygieneClinicalWorkPracticePatientMovement andTransfermulti-bedded ward post procedure.Procedures on an extrapulmonary TB open abscess or lesion whereaerosolisation of drainage fluid may occur should only be undertaken in anairborne isolation roomSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSHand hygiene is recommended;••••••Before and after each episode of patient contactBetween individual patient contactsAfter contact with blood, body fluids, secretions orexcretions, whether or not gloves are wornAfter handling soiled/contaminated equipment, materials orthe environmentImmediately before glove applicationImmediately after removing gloves or other protectiveclothingAntiseptic soap or alcohol gel if hands are physically clean before and afterpatient careHands should be decontaminated using soap and water or alcoholgel if physically clean. Antiseptic soap should be used prior toaseptic procedures.Patients should wash their hands after toileting and before meals.HCWs should assist those patients unable to perform hand hygieneindependently.Visitors should be educated on the importance of handdecontamination before and after visiting.(SARI) <strong>Guidelines</strong> on Hand Hygiene are available at www.hpsc.ie/hpsc/A-Z/Gastroenteric/Handwashing/STANDARD PRECAUTIONS AIRBORNE PRECAUTIONSNo special precautions recommended Limit movement and transport of patient to essential purposes onlyPrior to patient transfer•••Prior to accepting a patient with known or suspected infectious TB it is theresponsibility of the receiving facility to ensure compliance with isolationroom requirements as described above under patient placement. It isthe responsibility of the facility transferring the patient to provide theinformation.Inform transport personnel (emergency medical technicians, porters) andthe receiving department of the need for Airborne PrecautionsRequest patient to wear a surgical mask which should be changed whenheavily contaminated with respiratory secretions and/or wet or if torn.Instruct patient on respiratory hygiene and cough etiquette and ensurethe patient has a supply of tissues.-174-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticePatientMovement andTransferClinicalWorkPracticeRespiratoryEtiquette/CoughEtiquettedecontamination before and after visiting.(SARI) <strong>Guidelines</strong> on Hand Hygiene are available at www.hpsc.ie/hpsc/A-Z/Gastroenteric/Handwashing/STANDARD PRECAUTIONS AIRBORNE PRECAUTIONSNo special precautions recommended Limit movement and transport of patient to essential purposes onlyPrior to patient transfer•••••••Prior to accepting a patient with known or suspected infectious TB it is theresponsibility of the receiving facility to ensure compliance with isolationroom requirements as described above under patient placement. It isthe responsibility of the facility transferring the patient to provide theinformation.Inform transport personnel (emergency medical technicians, porters) andthe receiving department of the need for Airborne PrecautionsRequest patient to wear a surgical mask which should be changed whenheavily contaminated with respiratory secretions and/or wet or if torn.Instruct patient on respiratory hygiene and cough etiquette and ensurethe patient has a supply of tissues.HCWs should remove contaminated apron/gown/gloves (if worn) andmask and dispose prior to transporting patients. Staff do not need towear masks during internal transportation unless patient is unable to weara surgical mask (e.g. confused, respiratory distress).Ambulance staff should consider the use of FFP2 or FFP3 masks in thefollowing situations: (a) the patient is unable to wear a surgical mask; (b) itis anticipated that the duration of the journey will be ≥ 8 hours (≥ 4 hoursif HCW is immunocompromised); (c) if the patient has either MDR-or XDR-TB (consult infection prevention and control team in this situation).Don FFP2/3 mask prior to handling patient at the transport destination(e.g. X-ray, bronchoscopy suite)Transport equipment (stretcher, bed wheelchair) used to transport patientmust be cleaned and disinfected with a detergent and 1,000ppm ofavailable chlorine before use on another patientSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSAdministrative• Educate HCWs on the importance of control measures tocontain respiratory secretions to prevent droplet and contacttransmission of respiratory pathogens, especially duringseasonal outbreaks of viral respiratory tract infections (e.g.influenza, RSV, etc) in the community• Ensure that supplies of tissues, foot operating waste bins andhand hygiene facilities are available in all departments includingwaiting areas throughout the facilityNo extra precautions recommendedInformation for patients/visitors/public-175-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticeRespiratoryEtiquette/CoughEtiquette••Don FFP2/3 mask prior to handling patient at the transport destination(e.g. X-ray, bronchoscopy suite)Transport equipment (stretcher, bed wheelchair) used to transport patientmust be cleaned and disinfected with a detergent and 1,000ppm ofavailable chlorine before use on another patientSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSAdministrative• Educate HCWs on the importance of control measures tocontain respiratory secretions to prevent droplet and contacttransmission of respiratory pathogens, especially duringseasonal outbreaks of viral respiratory tract infections (e.g.influenza, RSV, etc) in the community• Ensure that supplies of tissues, foot operating waste bins andhand hygiene facilities are available in all departments includingwaiting areas throughout the facilityNo extra precautions recommendedInformation for patients/visitors/publicEducate patients/visitors/carers on respiratory etiquette and coughhygiene using some or all of the following:• Patient information leaflets• Welcome packs• Posters in all departments especially waiting areasAdditional precautions during times of increased prevalence ofrespiratory infections• During periods of increased prevalence of respiratory infectionsin the community, offer masks to coughing patients and othersymptomatic persons (e.g. persons who accompany ill patients)upon entry into the facility and encourage them to maintainspecial separation, ideally a distance of at least 3 feet, fromothers in common waiting areas• Some facilities may find it logistically easier to institute thisrecommendation year-round as a standard of practiceSee appendix 14 for sample poster for respiratory etiquette/coughetiquette-176-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticeUse ofPersonalProtectiveEquipment(PPE)ClinicalWorkPracticeUse ofPersonalProtectiveEquipment(PPE)STANDARD PRECAUTIONS AIRBORNE PRECAUTIONSType and selection ofPPEPPE consists of:• Gloves,• Aprons/gowns• Eye, nasal and mouth protectionAdditional respiratory protection required(see facial protection section)Each HCW should make an risk assessment of the planned procedureand select PPE depending on;• The nature of the procedure• The risk of exposure to blood and body fluids• The risk of contaminationGloves Gloves should be single use items and should conform to EuropeanCommunity StandardsNo extra precautions recommendedGloves are recommended;• For all activities that carry a risk of exposure to blood, body fluids,secretions or excretions, sharps or contaminated instruments• When touching mucous membranes and non-intact skin• When handling contaminated equipmentGloves should be;• Single use only• Sterile if contact anticipated with sterile body site• Put on immediately before an episode of patient contact andremove as soon as the activity is completed• Changed when caring for different patients and between differentcare activities on the same patient• Disposed of as health care risk waste if contaminated with blood orbody fluids from patients with suspected or known infection.Hand hygiene should be performed before donning and immediatelyfollowing removal of glovesSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSFaceprotectionFace protection should be worn where:•There is a risk of blood, body fluids,secretions or excretions splashing into theface or eyesIn addition to eye protection as required for Standard PrecautionsHCWs and visitors should don correctly fitted:• FFP2 masks before entering the isolation room of a suspected or confirmedinfectious TB case where MDR-TB not suspected-177-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticeUse ofPersonalProtectiveEquipment(PPE)ClinicalWorkPracticeUse ofPersonalProtectiveFaceprotectionAprons orgownsbody fluids from patients with suspected or known infection.Hand hygiene should be performed before donning and immediatelyfollowing removal of glovesSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSFace protection should be worn where:In addition to eye protection as required for Standard Precautions••There is a risk of blood, body fluids,secretions or excretions splashing into theface or eyesWhen placing a catheter or injecting intothe spinal or epidural space.Face protection consists of one of thefollowing:••••Fluid repellent mask with separategogglesRespiratory mask (FFP2/3)Face shieldFluid repellent mask with eye shield.Face protection should be:•Single use or single person use (faceshields and goggles can be reusedby the same HCW but they must beadequately cleaned and disinfected asper manufacturer’s instructions after eachuse.HCWs and visitors should don correctly fitted:• FFP2 masks before entering the isolation room of a suspected or confirmedinfectious TB case where MDR-TB not suspected• FFP3 mask during high risk procedures for all patients where TB is suspectedor confirmed (susceptible or MDR) such as:o Sputum inductiono Cough producing procedures (e.g. administering aerosolisedmedications, bronchoscopy, airway suctioning, endotracheal intubation)o Procedures where aerosolisation of drainage fluid from an abscess/lesions may occur• FFP3 masks before entering the isolation room of a suspected or known caseof MDR-TB or XDR-TBTo preserve privacy and confidentiality restricting visiting to immediate familyshould be discussed with the patientAll HCWs who may be required to use respiratory masks (FFP2 & FFP3) duringthe course of their work should be fit tested by a trained professional within eachorganisationHCWs should fit check the mask each time it is worn to check the sealHCWs visiting a patient in their own home should wear a FFP2 or FFP3 mask whilethe patient is infectious (see chapter 6 on Infection Prevention and Control fordiscontinuation of Airborne Precautions). Patient privacy must be maintained ifmask is worn in the home.All masks should be removed in the ante room or immediately outside the singleroom if there is no ante roomDiscard mask into healthcare risk wasteDecontaminate hands immediately after removing maskSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSDisposable aprons should be worn where there is a risk that the front ofuniform/clothing may become exposed to blood, body fluids, excretionsor secretionsNo extra precautions recommended-178-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticeUse ofPersonalProtectiveEquipment(PPE)ClinicalWorkPracticeEnvironmentalDecontaminationPatient CareEquipment &Decontamination ofMedical DevicesDiscard mask into healthcare risk wasteDecontaminate hands immediately after removing maskSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSAprons orgownsDisposable aprons should be worn where there is a risk that the front ofuniform/clothing may become exposed to blood, body fluids, excretionsor secretionsNo extra precautions recommendedLong sleeved fluid repellent gowns may be required if there is a riskthat uniform/clothing and skin may be exposed to blood, body fluids,excretions or secretionsRemoval of PPE Remove PPE when procedure is complete. PPE should be removedin the following order and disposed of into healthcare risk waste ifcontaminated with blood and/or body fluids••••••GlovesApron/gownDecontaminate handsEye wearMask (handle by the mask straps to avoid touching the front)Decontaminate handsAll masks should be discarded into healthcarerisk wasteSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSRoutine environmental cleaning is required to minimise the number of micro-organisms in theenvironment.Particular attention should be given to frequently touched surfaces and those most likelyto be contaminated with blood or body fluids e.g. bedrails, mattress, bedside tables,commodes, doorknobs, sinks, surfaces and equipment close to the patientChemical disinfectants are not recommended for routine environmental cleaningWhen using disinfectants, staff should follow the manufacturer’s instructions for dilution andcontact timesPatient care environment be cleaned anddisinfected with a detergent and 1000ppmof available chlorine daily before use onanother patient if contaminated withrespiratory secretions. PPE should be wornfor all cleaning procedures as per page 180-182.Room should remain vacant for one hourwith windows open before re-useRefer to National Hospital Office Cleaning Manual 2006Medical devices designated as “Single Use Only” must not be reprocessed or reused underany circumstances (MDA DB 2000), (MDD) 93/42/EECNo extra precautions recommendedNon-critical equipment-179-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticeEnvironmentalDecontaminationPatient CareEquipment &Decontamination ofMedical DevicesClinicalWorkPractice•••Eye wearMask (handle by the mask straps to avoid touching the front)Decontaminate handsSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSRoutine environmental cleaning is required to minimise the number of micro-organisms in theenvironment.Particular attention should be given to frequently touched surfaces and those most likelyto be contaminated with blood or body fluids e.g. bedrails, mattress, bedside tables,commodes, doorknobs, sinks, surfaces and equipment close to the patientChemical disinfectants are not recommended for routine environmental cleaningWhen using disinfectants, staff should follow the manufacturer’s instructions for dilution andcontact timesPatient care environment be cleaned anddisinfected with a detergent and 1000ppmof available chlorine daily before use onanother patient if contaminated withrespiratory secretions. PPE should be wornfor all cleaning procedures as per page 180-182.Room should remain vacant for one hourwith windows open before re-useRefer to National Hospital Office Cleaning Manual 2006Medical devices designated as “Single Use Only” must not be reprocessed or reused underany circumstances (MDA DB 2000), (MDD) 93/42/EECNo extra precautions recommendedNon-critical equipmentNon-critical equipment refers to equipment that is either not in contact with a patient or incontact with healthy skin. Such equipment should be:• In a state of good repair in order to facilitate effective cleaning• Must be thoroughly cleaned prior to use on another patient/resident. If soiled withblood or body fluids, disinfect using a chlorine-releasing solution of 1000ppm, orequivalent according to manufacturer’s instructions, rinse and dry.Reusable invasive medical devices (RIMD)RIMD refers to equipment that is classified as semi-critical or critical. RIMDs are in contactwith sterile body sites, mucous membranes and breaks in the skin. HCWs must ensure thatRIMDs are not used for another patient until they have been cleaned and reprocessedappropriately.(HSE Code of Practice for Decontamination of Reusable Invasive Medical Devices 2007)www.hse.ie/eng/Publications/Hospitals/Code_of_Practice_for_Decontamination_of_Reusable_Invasive_Medical_Devices_.htmlwww.hpsc.ie/hpsc/A-Z/MicrobiologyAntimicrobialResistance/CJD/Guidance/STANDARD PRECAUTIONS AIRBORNE PRECAUTIONS-180-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticeManagementof Health CareRisk WasteManagementof needle stickinjuries (NSI) andblood and bodyfluid exposureClinicalWorkPracticeReusable_Invasive_Medical_Devices_.htmlwww.hpsc.ie/hpsc/A-Z/MicrobiologyAntimicrobialResistance/CJD/Guidance/STANDARD PRECAUTIONS AIRBORNE PRECAUTIONSDispose of healthcare risk waste in accordance with the Department of Health & Children’s(DoHC) <strong>Guidelines</strong> for Waste Disposal, which outlines the categorisation and segregation ofhealthcare waste.Disposal of sharps;• Syringes and needles should be disposed of as a single unit• Used sharps should be carefully discarded into designated sharps bin at the point of use• Sharps bin should be securely stored out of reach of clients, visitors and children• Needles should not be re-capped, bent, broken or disassembled• Sharps should not be passed from person-to-person by handWaste contaminated with sputum from asuspected or known TB patient should bedisposed of as healthcare risk waste within ahealthcare facilityRespiratory masks should be disposed ofinto Healthcare risk wasteDoHC <strong>Guidelines</strong> on Disposal of Healthcare Risk Waste are available atwww.dohc.ie/publications/segregation_packaging.htmlAll facilities must have a local guideline on the management of needle stick injuries and bloodand body fluid exposure. This guideline should include;••••First aidRisk assessment and screening of source patient (if known)Risk assessment for chemoprophylaxisCounselling and follow up testingNo extra precautions recommendedFurther information fromwww.dohc.ie/publications/transmission_of_blood_borne_diseases_2006.htmlSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONS-181-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticeSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSLaundry care Laundry should be handled and transported in a manner that prevents transmission of micro-organisms toother patients, HCWs or the environmentNo extra precautions recommendedStaff handling soiled linen should wear gloves and a disposable plastic apronSegregation and transportation of used laundry should be in accordance with the guidelines from theSociety of Linen Services and Laundry Managers (2008)Staff should not manually sluice or soak soiled or infected linen/clothingLinen should be heat disinfected during the wash process by raising the temperature to either 65°C for notless than 10 minutes or preferably 71°C for not less than 3 minutes. Disinfection of heat labile materials(according to manufacturer instructions) can be achieved at low temperatures by introducing 150ppm ofchlorine into the penultimate rinse.ClinicalWorkPracticeSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSSpillages Spillages of blood, urine, faeces or vomit should be dealt with immediately wearing protective clothingNo extra precautions recommendedFor spillages of body fluid (e.g. urine, faeces or vomit);• Soak up as much of the visible material as possible with disposable paper towels• Dispose of the soiled paper towels according to national guidelines• Clean the area using warm water and general purpose neutral detergent• Disinfect using a chlorine-releasing solution of 1,000ppm, rinse and dry• Discard gloves and apron according to national guidelines• Decontaminate hands• Do not apply chlorine-based disinfectants directly onto spillages of urine as it may result in therelease of chlorine vapourFor blood spillages;• Decontaminate all blood spills with a chlorine based disinfectant (e.g. powder, granules or liquidcontaining 10,000ppm available chlorine) or suitable alternative, in line with the manufacturer’sinstructions and local policy• Wipe up the spillage with disposable paper towels and discard into a yellow healthcare risk bagor rigid container• Wash the area with a general purpose neutral detergent and water• Discard gloves and apron into healthcare risk bag• Decontaminate handsClinical STANDARD PRECAUTIONS AIRBORNE PRECAUTIONS-182-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCClinicalWorkPracticeSafeInjectionPracticesPracticesfor lumbarpunctureproceduresSTANDARD PRECAUTIONS AIRBORNE PRECAUTIONSAdministrationEducate all HCWs who administer injections on the importance of safe injection practicesAll facilities should have a guideline on the use of multi-dose vials.No additional precautions necessaryPreparation of InjectionsAll injections should be prepared in a clean area. This area must not be used for disposing of used needlesand syringes, handling blood samples or any material contaminated with blood or body fluidsAn aseptic technique must be used when drawing up injectionsNeedles, syringes and cannulae are sterile, single use items; they must not be reused for another patient norto access a medication or solution that might be used for a subsequent patientUse single dose vials wherever possibleDo not use single dose vials for multiple patientsDo not combine leftovers for later useMulti-dose vialsMulti-dose vials should only be used when absolutely necessaryRestrict wherever possible the use of multi-dose vials to a single patientLabel vial with patient’s name and date openedDiscard if sterility is compromised or questionableDo not leave multi-dose vials at a patient’s bedsideUse a sterile syringe and needle every time a medication vial is accessed even if it is a 2 nd dose of the samedrug for the same patient.Infusions and intravenous setsDo not use bags or bottles of intravenous fluids as a common source of supply for multiple patientsIntravenous fluids and intravenous sets are single use sterile items for use by a single patientConsider a syringe or needle/cannula contaminated once it has been used to enter or connect to a patient’sintravenous infusion bag or administration set.When inserting a catheter, injecting material/chemotherapy into the spinal canal or subdural space,healthcare workers should wear a surgical mask and adhere to aseptic technique.No additional precautions necessary-183-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 11: Discharge instructions for patients with potentiallyinfectious TBYou have been placed on medication to treat TB. You are now being discharged home from hospital.However, your TB may remain infectious (contagious) for some time longer. A number of generalinstructions and temporary restrictions are therefore being advised until it is certain that you are no longerinfectious to others. These restrictions will help reduce any possibility of spread of TB germs to otherpeople. You should follow them carefully until you are advised otherwise by the doctor who is treatingyour TB.General instructions:• Take your TB medications as instructed by your doctor• You should always cover your nose and mouth with a tissue when coughing or sneezing• Dispose of used tissues in a bin immediately after use and wash your hands• It is ok to share eating utensils (spoons, forks, cups or glasses) and other household items• Keep your doctor’s or clinic appointment so that you complete your treatment.Temporary restrictions after hospital discharge• Do not go to work or school and you should avoid going to any public areas (e.g. cinema, pubs orclubs, using public transport) until the doctor who is treating your TB says it is ok for you to do so.• If there are others living at home you should- limit the time you spend in common household areas (e.g. kitchen or living room) and keepyour bedroom door closed- If advised by your doctor to wear a surgical mask (as a temporary measure) that covers yournose and mouth (as explained to you in hospital) when you are around other people, follow theinstructions given. This will reduce the number of TB germs that you put into the air when youcough or talk.• You should not be around babies, young children or, to the best of your knowledge, people whohave weakened immune systems such as people with HIV/AIDS. (If there are young children athome, you may still be discharged home if the children have been tested for TB infection and arebeing followed up by the local public health department).These temporary restrictions will be removed once your doctor decides that you are no longer infectious.However, your TB treatment will continue until the course is completed.If you have any questions about your treatment, please call ……………………………….……Adapted with kind permission from Tuberculosis, Clinical Policies and Protocols. New York City Departmentof Health and Mental Hygiene (2008). Available from www.nyc.gov/html/doh/downloads/pdf/tb/tbprotocol.pdf.-184-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 12: List of Tuberculosis-related websites and resourcesNational TB WebsitesHealth Protection Surveillance Centrewww.hpsc.ie/hpsc/A-Z/VaccinePreventable/TuberculosisTB/Irish Thoracic Societywww.irishthoracicsociety.com/Immunisation <strong>Guidelines</strong> of Irelandwww.hpsc.ie/hpsc/A-Z/VaccinePreventable/Vaccination/Guidance/International TB WebsitesCenters for Disease Control and Prevention, USA, Division of TB Eliminationwww.cdc.gov/tb/Health Protection Agency, UKwww.hpa.org.uk/webw/HPAweb&Page&HPAwebAutoListName/Page/1191942150134?p=1191942150134The Public Health Agency of Canadawww.phac-aspc.gc.ca/tbpc-latb/index.htmlEuropean Centre for Disease Prevention and Controlwww.ecdc.europa.eu/Health_topics/Tuberculosis/Tuberculosis.htmlEuroTB: Surveillance of TB in Europewww.eurotb.org/WHO-Geneva Tuberculosis Homepagewww.who.int/tb/en/WHO-Euro Tuberculosis Sitewww.euro.who.int/tuberculosisThe Global Plan to Stop TBwww.stoptb.org/globalplan/WHO Stop TB Departmentwww.who.int/tb/about/en/index.htmlStop TB Partnershipwww.stoptb.org/The International Union against TB and Lung Diseasewww.iuatld.org/NICE: TB information for the Publicwww.nice.org.uk/nicemedia/pdf/CG033publicinfo.pdfTB Alertwww.tbalert.org/-185-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCTuberculosis GuidanceUKNICE Tuberculosis Clinical Guidancewww.nice.org.uk/search/guidancesearchresults.jsp?keywords=TUBERCULOSIS&searchType=guidanceControl and prevention of tuberculosis in the United Kingdom: Code of Practice 2000. JointTuberculosis Committee of the British Thoracic Society. Thorax 2000. Vol. 55, 11: 887-901www.thorax.bmj.com/cgi/reprint/55/11/887USACenters for Disease Control and Prevention (CDC) TB <strong>Guidelines</strong> (listed by category or by date)http://www.cdc.gov/tb/pubs/mmwr/maj_guide.htmCanadaCanadian Tuberculosis Standards 6th Edition, 2007www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdfNew ZealandNew Zealand TB <strong>Guidelines</strong>, 2003www.moh.govt.nz/moh.nsf/0/4760df3580a6f5b5cc256c86006ed394?OpenDocumentWorld Health OrganizationTuberculosis and Airflight (WHO)www.who.int/docstore/gtb/publications/aircraft/PDF/98_256.pdfWHO <strong>Guidelines</strong> for the programmatic management of resistant TBwww.whqlibdoc.who.int/publications/2006/9241546956_eng.pdfTreatment <strong>Guidelines</strong> for National Programmes – WHO Global Tuberculosis Programme, Genevawww.who.int/docstore/gtb/publications/ttgnp/<strong>Guidelines</strong> for the prevention of tuberculosis in health care facilities in resource limited settings –WHO Global Tuberculosis Programme, Genevawww.who.int/docstore/gtb/publications/healthcareWhat is DOTS? - Guide to the WHO recommended TB control strategywww.who.int/docstore/gtb/publications/whatisdotsScientific ResourcesMEDLINEplus Tuberculosiswww.nlm.nih.gov/medlineplus/tuberculosis.htmlFrancis J. Curry National Tuberculosis Centerwww.nationaltbcenter.edu/New Jersey Medical School Global Tuberculosis Institutewww.umdnj.edu/globaltb/home.htmStanford Center for Tuberculosis Research12www.stanford.edu/group/molepi/index.htmlBrown University TB/HIV Research Laboratorywww.brown.edu/Research/TB-HIV_Lab/The Public Health Research Institute (PHRI) Tuberculosis Centerwww.phri.org/programs/program_tbcenter.aspAeras Global TB Vaccine Foundationwww.aeras.org/-186-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCAppendix 13: Respiratory hygiene and cough etiquetteThese 3 steps will help prevent the spread of respiratory infectionsWhen coughing or sneezing use a tissue or cover your nose and mouthDispose of the tissues afterwards in a waste binDecontaminate your hands after discarding tissue using soap and water or alcohol gel-187-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCGlossary of TermsAcid-fast Bacilli: Bacteria which having been stained with a dye, retain their colour in acid alcohol. Usedas a technique for microscopic detection of mycobacteria. The relative concentration of AFB per unit areaon a slide (the smear grade) is associated with infectiousness. A positive culture is required for laboratoryconfirmation of M. tuberculosis complex.Active TB: Infection with mycobacteria of the M. tuberculosis complex, where mycobacteria are growingand causing symptoms and signs of disease. This is distinct from LTBI where mycobacteria are present butare inactive and not causing symptoms of disease. The diagnosis of active TB is made most often on thebasis of positive bacteriology but in approximately 15%-25% of cases on the basis of appropriate clinicaland/or radiological and/or pathological presentation as well as treatment response.Adherence: This refers to the patient’s ability or choice to adhere to a treatment regimenAerosol: Small droplets of moisture that are exhaled or coughed up. In a patient with pulmonarytuberculosis they may contain Mycobacterium tuberculosis bacteria that are suspended in the air andlead to the spread of infection. Generation of infectious aerosols is greatest with laryngeal and cavitarypulmonary disease.Air changes per hour (ACH): The number of air changes per hour in a room; one air change being avolume of air equal to the room volumeAirborne isolation: The conditions into which a patient with suspected or proven active tuberculosis maybe placed for purposes of preventing transmission to other persons. In most institutional settings airborneisolation is provided by a combination of increased ventilation (e.g. in the room occupied by the patient)and the use, by staff or visitors, of personal protective wear (respirators that filter 95% of particles of 1micron or larger and have less than 10% leak).Anergy: A condition wherein a person has diminished ability to mount a delayed T-cell hypersensitivityresponse to antigens because of a condition or situation resulting in altered immune function e.g. HIVinfection. When referring to an inability to react to a skin test, the correct term is “cutaneous anergy”.Bacille Calmette-Guerin (BCG) vaccine: A live attenuated vaccine derived from Mycobacterium bovis usedto prevent tuberculosis diseaseBAL: Bronchoalveolar lavage. This is a diagnostic procedure in which small amounts of physiologicalsolution (sterile saline solution) are injected through a fibreoptic bronchoscope into a specific area ofthe lung, while the rest of the lung is sequestered by an inflated balloon. The fluid is then aspirated andinspected for pathogens, malignant cells, and mineral bodies. BAL is typically performed to diagnose lungdisease.Booster phenomenon: The presence of an initially negative TST response followed by a positive responsewhen the test is repeated at any time from 1 week to 1 year later. The phenomenon often occurs manyyears after infection, most notably in the elderly. The initial negative response is based on the subject’sinitial failure to “recall” immunologically, prior infection. To avoid inadvertent labelling of a positiveresponse as due to TST conversion, especially when serial skin testing is planned, initial two-step skintesting may be recommended.Cavitary disease: This is a radiological-pathological label referring to evidence of lung destruction,i.e. evidence on chest X-ray or pathology of cavities or cystic areas that communicate with a bronchus.Cavities generally harbour large numbers of bacteria and, as a result, patients with cavitary disease tend tobe highly infectious.Chemopropylaxis: Treatment of LTBI. The administration of anti-tuberculosis drug (s) to prevent theacquisition of LTBI or progression of LTBI to active TB disease.-188-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCChemotherapy: The multidrug antibiotic treatment regimens used to treat active TBCompliance: see adherenceContact: A person identified as having come in contact with an active case of TB disease. The degree ofcontact is usually further defined as close and casual. The level and duration of contact usually suggests therisk of becoming infected.Contact tracing: The identification of contacts to find associated cases of TB disease, to detect peoplewith LTBI and to identify those not infected but for whom BCG vaccination might be appropriate.Conversion: A change in the result of a test for Mycobacterium tuberculosis infection that is interpreted toindicate a change from being uninfected to infected.Culture: The process of growing TB bacteria from sputum or other samples for identification and diagnosisCulture positive disease: The isolation of Mycobacterium tuberculosis complex (excluding BCG strain)from sputum, body secretions or tissueCure and completion rate: The proportion of people receiving treatment for active TB who either havenegative culture results during the continuation phase of treatment or who complete treatment withoutdocumented culture statusDirectly observed therapy (DOT): A way of helping patients to take their medicine for TB. A personreceiving DOT will meet with a healthcare worker everyday or several times a week at an agreed placee.g. the patient’s home, the TB clinic or other convenient location. The healthcare worker will observe thepatient taking their medication at this place helping to ensure that higher treatment completion rates areachieved. Sometimes someone in their family or a close friend will be able to help in a similar way to thehealthcare worker.Directly observed prophylaxis (DOP): The process whereby a health care worker or other responsibleadult e.g. family member or close friend watches the patient swallow each dose of medication for latenttuberculosis infection, helping to ensure higher treatment completion rates. DOP is also known as directlyobserved preventive therapy (DOPT). This definition is used in the Canadian Tuberculosis Standards, 6 thedition (2007).Directly observed therapy short-course (DOTS): The internationally recommended approach to TBcontrol, which forms the core of the World Health Organization (WHO) Stop TB Strategy ( 2006). The fivecomponents of DOTS are: political commitment with increased and sustained financing; case detectionthrough quality-assured bacteriology; standardised treatment with supervision and patient support;an effective drug supply and management system and a monitoring and evaluation system and impactmeasurementEarly morning specimen/sputum: Sputum from the first productive cough of the day (after waking)Elimination: The elimination of tuberculosis as a global public health problem, defined by the WHO StopTB Partnership (see www.stoptb.org/globalplan/) as an incidence of tuberculosis disease of less than 1 caseper million populationExtensively drug-resistant TB (XDR-TB): is resistance to at least isoniazid and rifampicin (i.e. MDR-TB),plus resistance to any fluoroquinolone, and any one of the following second line anti-TB injectable drugs(capreomycin, amikacin or kanamycin)Gamma–interferon test (interferon–gamma or IGRA): A blood test to diagnose LTBI (which may be usedas an alternative or an addition to tuberculin skin tests) based on detecting the response of white bloodcells to TB antigens-189-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCGastric washings: Some patients (particularly children) with suspected TB are unable to cough up anysputum. As an alternative, in a gastric lavage, saline solution is introduced into the stomach through atube, the contents are pumped out and are examined for M. tuberculosis complex bacteria.High incidence country: Any country with an incidence of TB ≥ 40 cases per 100,000 population per yearHistology: Microscopic examination of cells and clinical samplesIndex case: The initial person found to have TB whose contacts are traced. Consequently the source oftheir infection may be found, but the initial presenting patient is regarded as the index case.Induration: The soft tissue swelling that is measured when determining the TST response to purifiedprotein derivative (PPD) tuberculin. It is to be distinguished from erythema, which is not measured, i.e.does not constitute a measurable reaction to the antigen.Infectious: The condition whereby the patient can transmit infection to others by virtue of the productionof infectious aerosols. Those with smear-positive cavitary and laryngeal disease are usually the mostinfectious.Inform and advise information: Information provided to patients so that they are able to recognise thesymptoms of TB and be aware of the action they should take if these symptoms arise.Latent TB Infection: A person with LTBI usually has a positive TST or interferon gamma test but no physicalfindings of TB disease and the chest X-ray is normal or only reveals evidence of healed infection i.e.granulomas or calcification in the lung, hilar lymph nodes or both. Persons with LTBI are asymptomatic andare not infectious.Mantoux test: A type of TST in which tuberculin is injected intradermally. The injection site is examined forsigns of an immune response after 2-3 days. A negative Mantoux test is ≤ 5mm. The reaction to a TST isclassified according to the individual’s risk factors (table 2.1, chapter 2).Meta-analysis: A statistical technique for combining (pooling) the results of a number of studies thataddress the same question and report on the same outcomes to produce a summary result. The aim isto derive more precise and clear information from a large data pool. It is generally more reliably likely toconfirm or refute a hypothesis than individual trialsMycobacterium tuberculosis complex: The related mycobacterial species (M. tuberculosis, M. bovis, M.africanum, M. microti, M. canetii, M. caprae or M. pinnipedii) which cause tuberculosis in humansMultidrug-resistant TB (MDR-TB): TB bacilli resistant to at least isoniazid and rifampicin with or withoutresistance to ethambutol and streptomycinNon-tuberculous mycobacteria (NTM): All mycobacterial species except those that cause tuberculosis(Mycobacterium tuberculosis [including subspecies M. canetti], M. bovis, M. africanum, M.caprae, M.microti and M. pinnipedii) and those that cause leprosy (M. leprae). These mycobacteria are ubiquitous,often found in soil and water and are usually more clinically significant in the immunocompromised patient.They are also described as atypical mycobacteria.Nucleic acid amplification test: A test to detect fragments of nucleic acid allowing rapid and specificdiagnosis of M. tuberculosis directly from a range of clinical samplesNew entrant: Anyone coming to work or settle in Ireland. This will include immigrants, refugees, asylumseekers, students and people on work permits. This group may also include Irish born persons or Irishcitizens re-entering the country after a prolonged stay in a high incidence country.Polymerase chain reaction (PCR): The process whereby genetic material is amplified and subsequentlyevaluated for the presence of DNA material to identify various mycobacterial species-190-

<strong>Guidelines</strong> on the Prevention and Control of Tuberculosis in Ireland 2010HSE/HPSCReactivation: The advancement of old LTBI (whether previously detected or not) into active TBShort-course treatment: Modern 6 month treatment regimens for active TB (previously treatment hadbeen for at least 12 months)Smear: A laboratory technique for preparing a specimen so that bacteria can be visualised microscopically.The results for sputum acid-fast bacteria (AFB) smears typically are reported as numbers of AFB per highpoweredmicroscopy field, or else as a graded result from no AFB to 4+ AFB. The quantity of stainedorganisms is associated with the degree of infectiousness.Sputum: Mucous expelled from the bronchi and lungs by coughing (or retrieved from gastric washings,see above). Sputum is examined for TB bacteria by microscopic examination of stained smear; part of thesputum can also be used for culture.Sputum smear negative TB Case:A sputum smear negative TB case has:o At least three negative sputum smears (including at least one early morning specimen)o Chest X-ray findings consistent with tuberculosis ando Lack of response to a trial of broad-spectrum antimicrobial agents (Note: because thefluoroquinolones are active against M. tuberculosis complex and thus may cause transientimprovement in persons with tuberculosis, they should be avoided)It should be noted that in making a diagnosis based on the above three criteria, a clinician who decidesto treat with a full course of antituberculosis chemotherapy should report this as a case of sputum smearnegativepulmonary tuberculosis to the MOH.Sputum smear positive TB case: The revised WHO definition of a new sputum smear positive pulmonaryTB case is based on the presence of at least one acid fast bacilli (AFB+) in at least one sputum sample incountries with a well functioning external quality assurance (EQA) systemTreatment failure: Failure of the prescribed drug regimen to eliminate the TB bacteria from the body. Thisis demonstrated by a lack of clinical improvement or by positive culture after the end of the fourth monthof treatmentTuberculosis: Active TB; disease due to infection with M. tuberculosis complexTuberculin skin test: A test which involves the injection of tuberculin (purified protein derivative, PPD)into the skin. An immune reaction can be assessed after a few days according to the size of induration atthe injection site. The test can demonstrate acquired immunity to TB, lack of immunity or possible currentinfection (a strong response) but are confounded by immunosuppression, prior BCG vaccine, serial TST andprior exposure to atypical mycobacteria. The results are generally referred to as positive or negative.-191-

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25-27 Middle Gardiner Street Dublin 1 IrelandTel +353 1 876 5300 Fax +353 1 856 1299Email hpsc@hse.ie www.hpsc.ieThis report is also available to download at www.hpsc.ie